Previous changes

October 2025 — minor update. Typographical error corrected. 

September 2025 — minor update. Timing of post-dose lithium updated to 10-14 hours in line with Maudsley Prescribing guidance, 2025. Wording surrounding the use of contraception for men and boys on valporate has been updated to be more in line with NICE guidance. 

May 2025 — minor update. QOF indicators updated in line with the NHS England Quality and Outcomes Framework guidance for 2025/26.

February 2025 — minor update. Added detail relating to the NICE guidance Gambling-related harms: identification, assessment and management NICE, 2025🛈. Minor typographical error corrected. 

January 2025 — minor update. Severe cutaneous adverse reactions and hyperpigmentation added as adverse reactions for valproate, in line with the manufacturer's updated SPC.

September 2024 — reviewed and updated. A literature search was conducted in July 2024 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of this topic. No major changes to the recommendations have been made.

April 2024 — minor update. A minor typographical error has been corrected. 

January 2024 — minor update. A typographical error has been corrected. Information about the availability of MHRA safety and educational materials to reduce the risk of harm from valproate has been added to this topic.

August 2023 — minor update. Contact details for the UK Drugs in Lactation Advisory Service have been updated.

October 2022 — minor update. Information about a drug interaction between lithium and dapagliflozin has been added to this topic.

September 2022 — minor update. Valproate prescribing information updated based on SPC change. 

August 2022 — minor update. Removed prothrombin time as an annual monitoring requirement for sodium valproate. 

September 2021 — minor update. Cardiomyopathy, myocarditis, and cutaneous vasculitis have been reported as an adverse effect of quetiapine.

April 2021 — minor update. Some additional information on monitoring antipsychotics has been added to this topic.

February 2021 — minor update. Photosensitivity added as an adverse effect of lamotrigine in line with updated manufacturer's SPC.

November 2020 — minor update. New recommendation to monitor blood concentration of some antipsychotics has been added to the Antipsychotics Monitoring section.

March 2020 — minor update. Salivary hypersecretion has been added to the adverse effects of antipsychotic medications in line with manufacturer's SPC.

February 2020 — minor update. The recommendation that women or young girls of childbearing potential who are already taking valproate should be advised to gradually stop the medicine because of the risk of fetal malformations and adverse neurodevelopmental outcomes after any exposure in pregnancy was added to this topic in line with the updated NICE guideline Bipolar disorder: assessment and management.  

June 2019 — reviewed and updated. A literature search was conducted in June 2019 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of this topic. The topic has undergone restructuring. No major changes to the recommendations have been made.

September 2017 — minor update. Nimodipine added to the interactions section for valproate.

December 2016 — minor update.

• Drug Reaction associated with Eosinophilia and Systemic Symptoms (DRESS) has been added as an adverse effect of olanzapine. 
• Drug Reaction associated with Eosinophilia and Systemic Symptoms (DRESS) has been added as an adverse effect of lamotrigine.
• A Medicines and Healthcare products Regulatory Agency (MHRA) Drug safety update Valproate and risk of abnormal pregnancy outcomes: new communication materials recommendation to use new support tools to support discussion about the risks of valproate in pregnancy has been added to this topic.

October 2016 — minor update. Information added on reported cases of misuse and abuse with quetiapine.

October 2015 — minor update. Muscle weakness and rhabdomyolysis have been included as possible adverse effects of lithium.

May 2015 — minor update. Three updates based on updates to manufacturers' Summaries of Product Characteristics (SPCs):

• Mitochondrial disorders added as a contraindication to the use of valproate.
• Renal tumours (microcysts, oncocytomas, and collecting duct renal carcinoma) added as possible adverse effects of prolonged use (over 10 years) of lithium.
• Nightmares added as an adverse effect of lamotrigine.

March 2015 — minor update. Update to the text to incorporate the recommendation from the MHRA that valproate should not be prescribed to female children, female adolescents, women of childbearing potential or pregnant women unless other treatments are ineffective or not tolerated.

February 2015 — minor update. Diplopia added as an uncommon side effect with aripiprazole based on an update to the SPC.

July 2014 to November 2014 — reviewed. A literature search was conducted in May 2014 to identify evidence-based guidelines, UK policy, systematic reviews, and key RCTs published since the last revision of this topic. Changes have been made in line with the NICE guideline Bipolar disorder: the assessment and management of bipolar disorder in adults, children and young people in primary and secondary care.

July 2013 — minor update. Links to the DVLA website have been updated.

June 2013 — minor update. The 2013 QOF options for local implementation have been added to this topic.

April 2012 — minor update. The 2012/2013 QOF indicators have been added to this topic. 

February 2012 — minor update. New information about the rare association of quetiapine with diabetic ketoacidosis has been added. 

January 2012 — minor update. Relevant information from the Medicines and Healthcare products Regulatory Agency (MHRA) about a risk of extra-pyramidal effects or withdrawal symptoms (or both) in newborns after maternal use of anti-psychotics during the third trimester of pregnancy has been added to this topic. 

May 2011 — minor update. Relevant recommendations from the NICE guideline Psychosis with coexisting substance misuse have been incorporated into this topic. The 2011/2012 QOF indicators have also been added to this topic. Issued in June 2011.

June 2011 — interaction between SSRIs and tamoxifen added as stated in the most recent SPCs. 

February 2011 — topic structure revised to ensure consistency across CKS topics - no changes to clinical recommendations have been made.

October 2010 — minor update. Information on fitness to drive from the Driver and Vehicle Licensing Agency's guidance for medical practitioners, At a glance guide to the current medical standards of fitness to drive has been added. 

July 2010 — minor update. Prescribing information on Lithium updated to reflect new advice in the Summary of Product Characteristics (SPC) that one 5 mL spoonful of Priadel^®liquid (520 mg lithium citrate) is equivalent to 204 mg lithium carbonate, not 200 mg lithium carbonate as stated on previous SPCs.

June 2010 — minor update. Minor amendment to lithium prescribing issues (minor typographical error). 

January 2010 — minor update regarding interactions between lithium and antidepressants. 

December 2009 — minor update. The National Patient Safety Agency has developed a lithium patient information leaflet, a lithium alert card, and a record book for tracking blood tests. 

October 2009 — minor update. The Medicines and Healthcare products Regulatory Agency (MHRA) has reminded prescribers that smoking induces metabolism of olanzapine and clozapine, so stopping smoking can increase levels of these drugs, possibly causing increased adverse effects. 

May 2009 — minor update. The Quality and Outcomes Framework (QOF) indicators for stopping smoking related to bipolar disorder have been added to the QOF indicators section. 

September 2008 to February 2009 — this is a new CKS topic developed following a structured literature review. The evidence-base has been reviewed in detail, and recommendations are clearly justified and transparently linked to the supporting evidence.

New evidence

Evidence-based guidelines

• NICE (2025) Gambling-related harms: identification, assessment and management National Institute for Health and Care Excellence Homepage | NICE [Free full-text]

HTAs (Health Technology Assessments)

No new HTAs published since 1 July 2024.

Economic appraisals

No new economic appraisals relevant to England since 1 July 2024.

Systematic reviews and meta-analyses

• Mari, J., Dieckmann, L.H.J., Prates-Baldez, D., et al. (2024) The efficacy of valproate in acute mania, bipolar depression and maintenance therapy for bipolar disorder: an overview of systematic reviews with meta-analyses. BMJ Open. https://bmjopen.bmj.com [Free Full-text]

Primary evidence

No new primary evidence which reaches the CKS threshold for inclusion published since 1 July 2024.

New policies

No new national policies or guidelines since 1 July 2024.

New safety alerts

No new safety alerts since 1 July 2024.

Changes in product availability

No changes in product availability since 1 July 2024.

Basis for recommendation

The information on common presenting features of bipolar disorder is based on expert opinion within the International classification of diseases (ICD-10) [WHO, 1992], the Diagnostic and statistical manual of mental disorders (DSM-5) [APA, 2022], and the National Institute for Health and Care Excellence (NICE) guideline Bipolar disorder: assessment and management [NICE, 2023].

Unipolar and bipolar depression

• The advice that at onset, most people with bipolar disorder present with a depressive episode, and the information on the distinguishing features of unipolar and bipolar depression is based on expert opinion in  review articles [Grande, 2016; Nierenberg, 2023].
• The recommendation to ask about a history of overactive, or disinhibited behaviour in people who present with depression is based on the National Institute for Health and Care Excellence (NICE) guideline Bipolar disorder: assessment and management [NICE, 2023].
• The recommendation that symptoms of overactive or disinhibited behaviour should last at least 4 days is based on expert opinion from the Diagnostic and statistical manual of mental disorders (DSM-5) and International Classification of Diseases (ICD 10) which both require a minimum of 4 days of hypomanic symptoms to diagnose a hypomanic episode [WHO, 1992; APA, 2022].
• The questions suggested to elicit a history of mania or hypomania derive from expert opinion within a review article on bipolar disorder [Anderson, 2012].

Blood tests

• The advice to consider thyroid function tests, full blood count, vitamin D, or other blood tests (including a toxicology screen) to rule out differential diagnoses is based on expert opinion within the BMJ Best Practice guideline Bipolar disorder in adults [BMJ Best Practice, 2023] which states that:
  • Hyperthyroidism may mimic manic or hypomanic states.
  • Hypothyroidism can produce mental depression.
  • Serum vitamin D should be performed to exclude other possible causes of mood symptoms.
  • Toxicology screen should be performed to exclude other possible causes of mood symptoms — symptoms observed in manic, mixed, or hypomanic episodes may occur as part of an intoxication or withdrawal phenomenon from a drug of misuse.
• The recommendation to use clinical judgement to determine if any and which of these tests are required is pragmatic, based on what CKS considers to be good clinical practice.

Basis for recommendation

The information on the differential diagnoses of bipolar disorder is based on expert opinion in the National Institute for Health and Care Excellence (NICE) guideline Bipolar disorder: assessment and management [NICE, 2023], in the BMJ Best Practice guideline Bipolar disorder in adults [BMJ Best Practice, 2023], the British Association for psychopharmacology Evidence-based guidelines for treating bipolar disorder [Goodwin, 2016] and in narrative review articles [Anderson, 2012], [Grande, 2016; McIntyre, 2020].

How should I manage someone with bipolar disorder in primary care?

• Refer all people with suspected bipolar disorder to a specialist mental health service to confirm the diagnosis, treat the acute episode and establish a care plan. Clinical judgement should be employed to determine urgency of admission/referral, based on the results of an assessment of the risk of harm to the person and/or others:
  • For information on assessing severity of depression and risk of suicide, see the CKS topic on Depression. 
  • Determine the risks of harm to others by assessing:
    • The risk of neglect of people dependent on them for care, in particular family, children, and any other dependents. Follow local safeguarding procedures if appropriate.
    • Any risk to the public, especially if there is a risk of aggression or previous history of violence.
  • When determining the required urgency of admission/referral, also consider other potentially harmful consequences of poor judgment and associated actions that can occur during an acute episode, that may adversely effect the person's employment, personal relationships, and finances, and also the risks posed by driving, sexual activity, gambling, and alcohol/drug use.
    • If appropriate, ask about particular substance(s) used, quantity, frequency, and pattern of use, route of administration, and the duration of current level of use.
  • Refer for urgent mental health assessment if the person presents with mania, severe depression, or if they are a danger to themselves or other people. Also, consider that people with bipolar disorder may be vulnerable to exploitation or violence when in an abnormal mental state.
  • If the person needs to be admitted to the hospital, every attempt should be made to persuade them to go voluntarily. If the person refuses to go to hospital, compulsory admission may be necessary if the person:
    • Requires assessment and/or treatment in a hospital, and
    • Needs to be admitted in the interests of their own health or safety, and/or for the protection of other people.
    • Compulsory admission may be arranged under sections 2, 3, or 4 of the Mental Health Act. For further information, see the 'compulsory admission' section in the CKS topic on Depression. 
  • While awaiting specialist assessment:
    • Do not start antipsychotic medication unless on the advice from a consultant psychiatrist.
    • Consider tapering antidepressant medication on specialist advice if mania develops.
    • Advise the person to stop driving during the acute illness and that their insurance may not be valid if they continue to do so. For further information, see the DVLA 'At a glance guide'.
  • Be aware that abuse may be a contributory factor to, or cause of bipolar disorder in children. For further details on features that may indicate abuse, and how to act if abuse is suspected, see the CKS topic on Child maltreatment - recognition and management.
• For information on management strategies that may be implemented in secondary care, see the section on secondary care management.
•  People with confirmed bipolar disorder whose symptoms have responded effectively and remained stable following secondary care treatment may be offered the option to return to primary care for ongoing management, which may include:
  • Prescribing medication initiated in secondary care and undertaking any required monitoring. For further information, see the section on prescribing information.
    
    • Be aware that people under the age of 55 (including males) should only be initiated on valproate if two independent specialists have independently considered and documented that there is no suitable alternative treatment. Females of childbearing potential taking sodium valproate should be enrolled on a pregnancy prevention programme. Boys and men should be advised to use effective contraception (condoms, plus contraception used by a female sexual partner) throughout the valproate treatment period and for 3 months after stopping valproate.
  • Ensuring that the person has been offered appropriate psychological interventions that have either been developed specifically for bipolar disorder or in line with those recommended for the management of depression. For further information, see the CKS topic on Depression.
  • Monitoring the person's mood, and if necessary, following crisis plans developed in secondary care and liaising with secondary care specialists. For more information, see the section on managing relapse. 
  • Reviewing the person's physical health, mental health, and medication at least annually and more often if the person, carer or healthcare professional has any concerns. For more information, see the section on health checks for people with bipolar disorder.
  • Ensuring that people with bipolar disorder and their family and/or carers are informed about support available to help them back into work or education, their housing options, entitlement to benefits, and entitlement to drive.
    • Bipolar UK (www.bipolaruk.org.uk), MIND (www.mind.org.uk), and Rethink (www.rethink.org) have local self-help groups, and their websites provide practical advice.
    • For people who wish to find or return to work, ensure that supported employment programmes have been offered to them. The British Association for Supported Employment (base-uk.org) is the national trade association representing agencies involved in securing employment for people with disabilities. Jobcentres may also have disability advisers. Consider advising pre‑vocational training for people who are unable to work or unsuccessful in finding employment.
    • Inform the person that they must not drive during an acute episode, and that they must tell the Driver and Vehicle Licensing Agency (DVLA) about their illness. If they fail to do so their insurance may be invalid. For more detailed guidance, see guidance from the DVLA.
  • Ensuring that the person's family or carers:
    • Have ideally been offered an initial assessment of their own needs (done by mental health services) and a copy of the carer's care plan has been received by primary care.
    • Have ideally been offered a focused education and support programme.
    • Are aware of their right to a formal carer's assessment by social care services.
    • Know where to obtain help during a crisis. 
• If a person with bipolar disorder is being managed solely in primary care, re‑refer them to secondary care if:
  • There is a poor or partial response to treatment or treatment adherence is poor.
  • The person's functioning declines significantly.
  • They develop intolerable or medically important side effects from medication.
  • Comorbid alcohol or drug misuse is suspected.
  • The person is considering stopping any medication after a period of relatively stable mood.
  • A female of reproductive potential with bipolar disorder is taking sodium valproate without two specialists having independently considered and documented that there is no other effective or tolerated treatment, as a change of medication should be considered.
  • A woman with bipolar disorder is pregnant or planning a pregnancy. For further information, see the section on pregnancy.

How should I manage people with known bipolar disorder who relapse?

• For adults with an established diagnosis of bipolar disorder who relapse, undertake an assessment of the risk of harm to the person and/or others.
• For adults who have a care plan or equivalent — manage according to the care plan and, where possible, comply with their advance statement or crisis plan.
  
  • The advance statement and statement of wishes and feelings are written and signed when the person is well. It sets out how they would prefer to be treated (or not treated) if they were to become ill in the future.
  • If in doubt about how to proceed, seek advice from the key clinician or care coordinator stated in the crisis plan.
• For adults who do not have a care plan or equivalent:
  • If the person develops mania or severe depression and is judged to be at immediate risk of harm to themselves or others, arrange same-day specialist assessment by the local crisis resolution and home treatment team.
    • If the person needs to be admitted to the hospital, every attempt should be made to persuade them to go voluntarily. 
    • If admission is necessary but the person declines compulsory admission may be an option. For further information, see the 'compulsory admission' section in the CKS topic on Depression. 
  • If the person develops mania or severe depression and is not judged to be at immediate risk of harm to themselves or others, urgently refer for a specialist assessment by the community mental health service.
  • If the person develops signs of hypomania or deterioration of depressive symptoms, refer them for a specialist assessment by the community mental health service or seek specialist advice.
• Whilst awaiting specialist assessment, do not alter or start treatment except on specialist advice.
• Children and adolescents should be under the care of specialist mental health services. If a relapse is suspected, seek specialist advice.

What routine health reviews are required for people with bipolar disorder?

• Children and adolescents should only be treated by specialists and should have ongoing management in secondary care.
• For adults being managed in primary care, assess the person's mental and physical health at least annually, or assess mental health more regularly:
  • If the person or their carer expresses any concerns.
  • If there is sleep disturbance.
  • After significant life events, such as loss of a job or bereavement.
• Develop and use practice case registers to monitor the physical and mental health of people with bipolar disorder in primary care.
• When carrying out a mental health review:
  • Assess symptom control by asking about symptoms of mania, hypomania, or depression, and seek specialist advice regarding ongoing management if needed.
  • Assess for early warning signs of relapse. Symptoms usually occur around two to four weeks before an episode of mania or depression regardless of the severity. A list of early warning signs for the person can be established by reviewing the run-up to previous relapses.
  • Give advice on preventing relapse, for example:
    • Encouraging compliance with treatment.
    • Maintaining an adequate amount of sleep.
    • Avoidance, if possible, of shift work, night flying and flying across time zones, or routinely working excessively long hours.
    • Establishing a regular routine in the morning.
    • Structuring the day with some activity and social contact.
    • Self-monitoring of symptoms (including triggers and early warning signs) and coping strategies.
    • Avoiding caffeinated drinks such as tea, coffee, or cola.
    • Smoking — advise the person to stop, or if this is not possible cut down (nicotine is a stimulant).
    • Avoiding alcohol and drug misuse.
• When carrying out a physical health review:
  • Ask about symptoms that could be due to adverse effects of medication. See the section on Prescribing information for more information.
  • Ensure that there are arrangements in place for monitoring of lithium, valproate, and antipsychotics (if applicable).
    • Ensure that females of childbearing potential taking sodium valproate are enrolled on a pregnancy prevention programme (including use of reliable contraception) and that two specialists have independently considered and documented that there is no other effective or tolerated treatment.
    • Ensure that males of reproductive potential taking sodium valproate are advised to use effective contraception and that two specialists have independently considered and documented that there is no other effective or tolerated treatment.
  • Ask about alcohol intake and substance misuse, and encourage people who smoke to stop. Note that smoking enhances the metabolism of olanzapine and clozapine.
    • For more information, see the CKS topics on Smoking cessation, and Alcohol - problem drinking.
  • Ask about the person's diet, and level of physical activity, check the person's weight, and measure their waist circumference.
  • Measure the person's pulse and blood pressure, and assess and manage the person's cardiovascular risk. For more information, see the CKS topic on CVD risk assessment and management.
  • In addition, assess for respiratory conditions such as chronic obstructive pulmonary disorder (COPD) if appropriate.
  • Perform the following blood tests:
    • Fasting glucose, HbA1_c.
    • Lipid profile.
    • Urea and electrolytes.
    • Full blood count.
    • Liver function tests.
    • Thyroid function and calcium levels if the person is taking long-term lithium.
• Manage as appropriate people identified as having hypertension, abnormal lipid levels, obesity (or those at risk of obesity), diabetes (or risk of diabetes as indicated by abnormal blood glucose levels). For more information, see the CKS topics on Hypertension, Lipid modification - CVD prevention, Obesity, and Diabetes - type 2.
• Send a copy of the results of the annual physical health review to the person's care co-ordinator and/or psychiatrist.
• Attempt to make contact with people who do not attend a review appointment (within 14 days).
  • If it is not possible to make contact despite reasonable efforts to do so, inform the person's care coordinator (who may be their psychiatrist, community psychiatric nurse, or social worker).

How should I manage a woman with bipolar disorder who is planning a pregnancy or presents with an unplanned pregnancy?

• Refer women who are pregnant or planning a pregnancy to a specialist perinatal mental health service if available or to the community mental health service for an assessment and discussion of drug treatment.
  • Note: NICE recommends that if women or young girls of childbearing potential are already taking valproate, they should be advised to gradually stop the medicine because of the risk of fetal malformations and adverse neurodevelopmental outcomes after any exposure in pregnancy. The dose of valproate should be reduced gradually over at least 4 weeks to minimise the risk of relapse. 
• Do not alter or stop drug treatment without seeking specialist advice.
  • Explain to the woman that she may be advised to:
    • Remain on her current drug treatment throughout conception, pregnancy, and birth.
    • Switch to another drug treatment.
    • Stop or reduce the dose of her medication.
  • Explain that the strategy which is chosen will depend on her wishes and on the advice of the medical team, who need to balance the risks of under-treatment (relapse) with the risk of harming the fetus by remaining on drug treatment.
  • Discuss the likelihood that sleep and routine will be disturbed after the baby is born. Participate in multi-agency plans for practical support after the baby is born (from the woman's family, health visitor, organizations such as Sure Start, and social care) so that the woman gets enough rest and sleep.
• Note: the Medicines and Healthcare Products Regulatory Agency (MHRA) recommends that valproate should not be prescribed to pregnant women to treat bipolar disorder unless the illness is very severe and there is no effective alternative option. Valproate is a teratogen and can cause physical birth defects and developmental disorders in children exposed in utero.
  • The MHRA has produced safety and educational materials for men and women and healthcare professionals to reduce the risk of harm from valproate, including the risk of serious harm to the baby if taken during pregnancy and the risk of impaired fertility in males.
• For women who are planning a pregnancy, give general pre-conception advice (such as cessation of smoking and alcohol consumption) and prescribe folic acid. Note that high dose (5 mg/day) is indicated in women taking certain medications and who are obese.
  • For more detailed information, see the CKS topic on Pre-conception - advice and management.

What issues should I consider if a woman is breastfeeding?

• Support a woman with bipolar disorder in the choice of feeding method that best suits her and her family. Breastfeeding may be appropriate unless the woman is taking lithium (note: breastfeeding is also not advised in women taking carbamazepine or clozapine, but these are rarely used to treat bipolar disorder).
• If more advice on breastfeeding and medication is required, liaise with specialist mental health services or seek specialist advice from the UK Drugs in Lactation Advisory Service — ukdilas.enquiries@nhs.net or telephone 0116 2586491. 

General information

• The most commonly prescribed antipsychotics to treat bipolar disorder are second generation antipsychotics such as olanzapine, quetiapine, and risperidone.
• An antipsychotic may be used in monotherapy or prescribed concurrently with lithium or valproate. 
• CKS recommends that people requiring a change in the dose of their antipsychotic or a change of drug should be referred to specialist mental health services, or that specialist advice should be sought.
• When discontinuing antipsychotics, the dose should be reduced gradually over at least 4 weeks if the person is continuing with other antimanic drugs. If the person is not continuing with other antimanic drugs or if there is a history of manic relapse, a withdrawal period of up to 3 months should be considered.

[BNF, 2024]

How should I monitor someone taking antipsychotics?

• When antipsychotics are initiated, baseline measurements should be taken in secondary care. Many adults with bipolar disorder will remain under the responsibility of the secondary care team for the first 12 months, or until their condition has stabilized (whichever is longer).
• Regular monitoring may subsequently be done in primary care on specialist advice or depending on the person's care plan. This may include:
  • Body weight, or body mass index (BMI) - weekly for the first 6 weeks, then at 3 months. Thereafter every 12 months, or more often if the person is gaining weight rapidly.
  • Serum electrolytes and urea including creatinine and estimated glomerular filtration rate - every 12 months.
  • Full blood count - every 12 months.
  • Blood lipids - 3 months after starting treatment, then every 12 months.
  • Plasma glucose or HbA1c — 3 months after starting treatment, then every 12 months. Additionally for clozapine and olanzapine, repeat after the first month of treatment, ideally by oral glucose tolerance test or fasting plasma glucose (HbA1c if fasting not possible). Ask about symptoms of hyperglycaemia (such as polydipsia, polyuria, and increased appetite).
    • In some cases both plasma glucose and HbA1c may be monitored.
  • Pulse and blood pressure - during dose titration and at each dose change.
    • Not required for amisulpride, aripiprazole, trifluoperazine, and sulpiride.
  • Electrocardiography (ECG) - after dose changes. Ideally, also annually.
    • Mandatory for haloperidol, pimozide, and sertindole; not required for antipsychotics with no effect, or a low-to-moderate effect on the QT interval and where there are no other risk factors for arrhythmia.
  • Prolactin - 6 months after starting treatment, then every 12 months. Also ask about symptoms of raised prolactin (these include low libido, sexual dysfunction, menstrual abnormalities, gynaecomastia, and galactorrhoea).
    • Not required for aripiprazole, clozapine, quetiapine, or olanzapine (less than 20 mg daily), unless symptoms of hyperprolactinaemia are present.
  • Liver function tests - every 12 months.
  • Creatinine kinase if neuroleptic malignant syndrome is suspected.
  • Monitoring for the emergence of movement disorders.
• Tests which need to be done every 12 months may be carried out at the annual physical review.
• Note: following fatal cases involving toxicity of clozapine and other antipsychotic medicines, monitoring blood concentration of amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and sulpiride may be helpful in certain circumstances, such as where people present with symptoms suggestive of toxicity, or when concomitant medicines may interact to increase blood concentration of these medicines.
• Clozapine
  • People taking clozapine are managed exclusively in secondary care. Clozapine can cause neutropenia or agranulocytosis, and frequent monitoring of the full blood count is required. This is carried out by the clozapine monitoring service.
  • Clozapine has been associated with varying degrees of impairment of intestinal peristalsis, ranging from constipation, which is very common, to very rare intestinal obstruction, faecal impaction, and paralytic ileus. People taking clozapine and their carers should be advised to seek immediate medical advice before taking the next dose of clozapine if constipation develops.
  • It is recommended that people taking clozapine who stop smoking (including switching to an E-cigarette) undergo monitoring of blood concentration of clozapine for toxicity.

[NICE, 2023; BNF, 2025]

What are the contraindications and cautions?

Intramuscular use of olanzapine is contraindicated in people with:

• Acute myocardial infarction.
• Bradycardia.
• Recent heart surgery.
• Severe hypotension.
• Sick sinus syndrome.
• Unstable angina.

Antipsychotics should be used with caution in people with:

• Blood dyscrasias.
• Cardiovascular disease.
• Conditions predisposing to seizures; epilepsy.
• Depression.
• Diabetes (may raise blood glucose).
• History of jaundice.
• Myasthenia gravis.
• Parkinson’s disease (may be exacerbated).
• Photosensitisation (may occur with higher dosages).
• Prostatic hypertrophy.
• Severe respiratory disease.
• Susceptibility to angle-closure glaucoma.

[BNF, 2024]

What adverse effects of antipsychotics should I be aware of?

• Antipsychotics can cause a wide range of adverse effects. The risk varies with the type of antipsychotic (first-generation or second-generation) and the individual drug. Adverse effects include:
  • Extrapyramidal symptoms - more common with first-generation antipsychotics. They include:
    • Dystonic reactions (abnormal movements of the face and body), and pseudoparkinsonism (tremor, bradykinesia, and rigidity) - these can be alleviated by antimuscarinic drugs, such as procyclidine (should not be prescribed routinely).
    • Akathisia (motor restlessness) - can often be relieved by reducing the dose of the antipsychotic.
    • Tardive dyskinesia - late-onset movement disorder that can occur with prolonged use of antipsychotics. It is characterized by rhythmical, involuntary movements, usually lip-smacking and tongue rotating, although it can affect the limbs and trunk. It may be persistent and can sometimes worsen on treatment withdrawal. The drug should be discontinued on appearance of early signs.
    • Oculogyric crisis has been reported as an adverse effect of aripiprazole.
  • Weight gain - common with all antipsychotics, but more frequent with second-generation antipsychotics. In general, clozapine and olanzapine have the greatest potential to cause weight gain, followed by chlorpromazine, quetiapine, and risperidone.
  • Dyslipidaemia - phenothiazines (such as chlorpromazine), clozapine, olanzapine, quetiapine, and risperidone all increase lipid levels. Offer dietary advice and consider treatment with a statin according to national guidelines.
  • Hyperprolactinaemia - most antipsychotics can cause hyperprolactinaemia that may lead to galactorrhoea, amenorrhoea, gynaecomastia, hypogonadism, sexual dysfunction, and an increased risk of osteoporosis. Clozapine, olanzapine, quetiapine, and aripiprazole do not increase prolactin above the normal range in standard doses.
  • Sedation - chlorpromazine, clozapine, promazine, and zotepine cause the highest incidence of sedation. Amisulpride, aripiprazole, sertindole, and sulpiride are associated with a very low incidence of sedation. Performance of skilled tasks (such as driving) may be affected; effects of alcohol are enhanced. Tolerance to sedation usually develops.
  • Anticholinergic effects (such as dry mouth, blurred vision, urinary retention, constipation, and cutaneous flushing) — chlorpromazine and clozapine have potent anticholinergic effects. Tolerance may develop, but it is very variable, and these adverse effects are often poorly tolerated.
  • Postural hypotension - commonly associated with clozapine, chlorpromazine, aripiprazole, quetiapine, and risperidone.
  • Hypertension - commonly reported with clozapine but there are also reports with aripiprazole, olanzapine, quetiapine, and risperidone. Hypertension can occur as:
    • A small, steady increase in blood pressure over time (may be associated with weight gain), or
    • An unpredictable, sharp increase in blood pressure on starting a new drug.
  • Reduced seizure threshold - seizures are a recognized adverse effect of antipsychotics (the higher the dose, the greater the risk). Clozapine carries the greatest risk.
  • Impaired glucose tolerance - has been associated with both first-generation and second-generation antipsychotic drugs. Hyperglycaemia, and sometimes diabetes (including ketoacidosis and coma) can occur in people taking clozapine, olanzapine, risperidone, and quetiapine.
  • Cardiomyopathy, myocarditis, and cutaneous vasculitis – these have been reported with quetiapine, but a causal relationship has not been established. Consider discontinuing treatment if cardiomyopathy or myocarditis are suspected. 
  • QT interval prolongation - the most widely reported cardiac conduction defect caused by antipsychotics and considered to be a class effect. However aripiprazole and paliperidone are thought to have no effect on the QT interval.
    • Avoid co-prescribing other drugs that are known to prolong the QT interval (for example tricyclic antidepressants, erythromycin, or antiarrhythmics), and monitor potassium levels at least annually as there is an increased risk of arrhythmia if the person has hypokalaemia.
    • People taking antipsychotics who experience palpitations or any other symptoms that suggest cardiac disease should undergo electrocardiography.
  • Stroke risk - olanzapine and risperidone have been associated with an increased risk of stroke in elderly people with dementia. The Committee on Safety of Medicines advised that:
    • For acute psychotic conditions in elderly people with dementia, risperidone should be limited to short-term use under specialist advice; olanzapine is not licensed for acute psychosis.
    • The possibility of cerebrovascular events should be considered carefully before treating people with a history of stroke or transient ischaemic attack; risk factors for cerebrovascular disease (for example hypertension, diabetes, smoking, and atrial fibrillation) should also be considered.
  • Venous thromboembolism (VTE) - antipsychotic use may be associated with an increased risk of VTE.
    • Data are insufficient to determine any difference in risk between second-generation and first-generation antipsychotics, or between individual drugs.
    • All possible risk factors for VTE should be identified before and during antipsychotic treatment and preventive measures undertaken.
  • Neuroleptic malignant syndrome (NMS)- is a rare but potentially fatal adverse effect of all antipsychotics. Signs and symptoms of NMS include fever, increased sweating, rigidity, confusion, fluctuating consciousness, fluctuating blood pressure, tachycardia, raised creatine kinase, leucocytosis, and raised liver function tests.
  • Pneumonia - recent evidence from observational studies suggest that all antipsychotics are associated with an increased risk of pneumonia. The mechanism by which this occurs is unclear.
  • Neutropenia - stop the suspected drug if neutrophils fall below 1.5 x 10⁹/L and seek urgent advice from a secondary care specialist.
  • Abnormal liver function tests (LFTs) - stop the suspected drug if LFTs suggest hepatitis (transaminases rise to three times normal) or prothrombin time or albumin are abnormal. Seek advice from a secondary care specialist.
  • Photosensitivity - is common with chlorpromazine. Adequate use of sunscreen should prevent sunburn in affected people. Some high-factor sunscreens (sun protection factor 30 or above) are available on prescription. The prescription should be endorsed with ACBS.
  • Skin and subcutaneous tissue disorders - olanzapine has been associated with Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), frequency unknown.
  • Diplopia - is an uncommon side effect with aripiprazole.
  • Misuse and abuse - cases of misuse and abuse have been reported with quetiapine. Quetiapine should be prescribed with caution in people who have a history of drug or alcohol abuse.
  • Salivary hypersecretion.

[CSM, 2004; Taylor, 2021; EMC, 2023a; EMC, 2023b; BNF, 2024; EMC, 2024a]

What are the drug interactions of antipsychotics?

• The following interactions are common to all antipsychotics:
  • Drugs with a sedative action (such as alcohol, analgesics, tricyclic antidepressants, and sedating antihistamines) will enhance the sedative effects of antipsychotics.
  • Drugs with a hypotensive effect (for example antihypertensives) will enhance the hypotensive effect of antipsychotics.
  • Drugs that prolong the QT interval, such as anti-arrhythmics, macrolides (for example erythromycin), and tricyclic antidepressants, may have a synergistic effect on the QT interval. Avoid co-prescribing drugs that prolong the QT interval. These drugs are contraindicated with haloperidol, sertindole, or pimozide therapy.
  • Diuretics may cause hypokalaemia, which may increase the risk of arrhythmias; monitor potassium levels in people taking diuretics.
• Azole antifungals
  • Azole antifungals may increase levels of some antipsychotics, for example:
    • Aripiprazole levels are predicted to be increased by itraconazole.
    • Haloperidol levels are increased by 30% or more by itraconazole.
  • If azole antifungals are given concurrently with antipsychotics, monitor for signs of adverse effects of antipsychotics and consider reducing the dose as necessary.
  • The manufacturer of aripiprazole recommends halving the dose of aripiprazole if itraconazole is given concomitantly.
• Carbamazepine
  • Carbamazepine reduces plasma levels of clozapine, haloperidol, and risperidone by half. Carbamazepine also reduces levels of aripiprazole, fluphenazine, olanzapine, quetiapine, and sertindole.
    • Monitor the person's symptoms to ensure that antipsychotics remain effective.
  • Carbamazepine levels are increased by haloperidol, quetiapine, or risperidone, or chlorpromazine with amoxapine.
    • Monitor carbamazepine levels if these drugs are given together.
• Grapefruit juice
  • Advise the person not to drink grapefruit juice if they are taking pimozide. Grapefruit juice increases the levels of pimozide, possibly leading to torsades de pointes potentially fatal arrhythmias.
• Selective serotonin reuptake inhibitors (SSRIs)
  • SSRIs increase levels of some antipsychotics, for example:
    • Haloperidol levels are increased by 20–30% by fluoxetine and by 20–60% by fluvoxamine.
    • Risperidone levels are increased by fluvoxamine, fluoxetine, and paroxetine.
    • Sertindole levels are increased two- to three-fold by fluoxetine and paroxetine.
    • Clozapine and olanzapine levels are increased by fluoxetine, fluvoxamine, paroxetine, sertraline, and possibly citalopram.
  • Where antipsychotic drug levels are increased, the person should be monitored and the dose adjusted accordingly.
• Stopping smoking
  • Smoking induces the metabolism of olanzapine and clozapine. If the person stops smoking, monitor for increased adverse effects and seek advice about dose adjustment if necessary [MHRA, 2009]. It is recommended that people taking clozapine who stop smoking (including switching to an E-cigarette) undergo monitoring of blood concentration of clozapine for toxicity.

[EMC, 2023a; EMC, 2023b; BNF, 2024; EMC, 2024a; Preston, 2024]

Contraindications and cautions

Prescribe lamotrigine with caution to people with:

• Myoclonic seizures (may be exacerbated).
• Parkinson’s disease (may be exacerbated).

[BNF, 2024]

What are the adverse effects of lamotrigine?

Adverse effects of lamotrigine include:

• Skin rash:
  • All people (adults and children) who develop a rash should be promptly evaluated and lamotrigine withdrawn immediately unless the rash is clearly not drug related.
  • Rash has been reported in up to 12% of people taking lamotrigine in clinical trials . These rashes were maculopapular in appearance, generally appeared within 8 weeks of starting treatment, and resolved on withdrawal of lamotrigine.
  • Serious, potentially life threatening skin rashes, including Stevens–Johnson syndrome, toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. Stevens–Johnson syndrome has been reported in 0.3% of adults and 0.8% of children.
  • In children, the initial presentation of a rash can be mistaken for an infection; clinicians should consider the possibility of a drug reaction in children that develop symptoms of rash and fever during the first 8 weeks of therapy.
  • Factors associated with increased risk of serious skin reactions include:
    • Concomitant use of valproate, initial lamotrigine dosage higher than recommended, and more rapid dose escalation than recommended.
    • Rash is sometimes associated with hypersensitivity syndrome (fever, lymphadenopathy, hepatic dysfunction, blood disorders, disseminated intravascular coagulation, and multiorgan dysfunction) and is more common in people with a history of allergy or rash from other antiepileptic drugs.
• Other adverse effects reported include nausea, vomiting, diarrhoea, dry mouth, aggression, agitation, headache, dizziness, drowsiness and insomnia, diplopia, blurred vision, conjunctivitis, confusion, nightmares, and hallucinations.
• Some rarely reported adverse effects include:
  • Hypersensitivity syndrome.
  • Photosensitivity.
  • Blood disorders: leucopenia, thrombocytopenia, pancytopenia.
  • Lupus-like reactions.
• There is a small risk of suicidal thoughts and behaviour, which may be seen as early as one week after starting treatment.
  • People taking lamotrigine and healthcare professionals should be alert to any mood changes, distressing thoughts, or feelings about suicide or harming themselves at any point during treatment.

[MHRA, 2008; EMC, 2023c; BNF, 2024]

What are the drug interactions of lamotrigine?

Key drug interactions with lamotrigine include:

• CNS depressants — enhanced effect when co-administered with lamotrigine.
• Carbamazepine, rifampicin, phenytoin, primidone, oestrogens, and progestogens —plasma concentration of lamotrigine is reduced and the dose may therefore need to be increased.
• Desmopressin — Lamotrigine is predicted to increase the risk of hyponatraemia when given with desmopressin. Manufacturer advises monitor serum sodium.
• Ritonavir — Ritonavir slightly decreases the exposure to lamotrigine. Manufacturer advises monitor lamotrigine concentration.
• Valproate — Plasma concentration of lamotrigine is increased by valproate. Manufacturer advises adjust lamotrigine dose and monitor for rash.

[EMC, 2023c; BNF, 2024]

How should I prescribe lithium?

• Always prescribe lithium by brand name as preparations vary widely in bioavailability.
  • Lithium is available as two salts, lithium carbonate and lithium citrate, which are not dose equivalent.
    • Lithium carbonate is supplied in tablet form (Camcolit^®, Liskonum^®, and Priadel^®).
    • Lithium citrate is supplied as a liquid (Priadel^® liquid and Li-Liquid^®).
    • One 5 mL spoonful of Priadel^® liquid (520 mg lithium citrate) is equivalent to 204 mg lithium carbonate.
    • One 5 mL spoonful of Li-Liquid^® (509 mg lithium citrate) is equivalent to 200 mg lithium carbonate. Note that Li-Liquid® is also available in a 1.018 g/ 5 mL preparation.
  • All lithium preparations vary widely in bioavailability and lack of clarity over which preparation is intended can lead to the person receiving a subtherapeutic or toxic dose.
• The lithium dose is usually adjusted to achieve a plasma level of 0.6 mmol/L to 1 mmol/L.
  • A serum lithium level of 0.6–0.8 mmol/L is suitable for people who are being prescribed lithium for the first time.
  • Higher serum lithium levels (0.8–1.0 mmol/L) are suitable for people who have relapsed previously while taking lithium, or who still have sub-threshold symptoms with functional impairment while receiving lithium.

[NICE, 2023; BNF, 2024]

What are the contraindications and cautions?

• Do not prescribe lithium to people with:
  • Cardiac disease associated with rhythm disorders.
  • Clinically significant renal impairment.
  • Untreated or untreatable hypothyroidism.
  • Brugada syndrome or family history of Brugada syndrome.
  • Low sodium levels, including people that are dehydrated and those on low-sodium diets.
  • Addison's disease.
• Lithium should also be avoided in people:
  • With a history of diabetes insipidus.
  • Who refuse regular blood tests.
  • Who are at high risk of taking a lithium overdose (intentional or unintentional).
  • Who are breastfeeding.
• Prescribe lithium with caution to people:
  • With cardiac disease.
  • Receiving concurrent electroconvulsive therapy (ECT) — may lower seizure threshold.
  • Receiving diuretic treatment (risk of toxicity).
  • Who are elderly (reduce dose).
  • With epilepsy (may lower seizure threshold)
  • With myasthenia gravis.
  • With psoriasis (risk of exacerbation)
  • With QT interval prolongation.
• Review the lithium dose as necessary in people:
  • With diarrhoea.
  • With intercurrent infection (especially if sweating profusely).
  • Who are vomiting.
  • Following surgery.

[NICE, 2023; BNF, 2024]

What are the adverse effects of lithium?

• Initial adverse effects of lithium therapy include nausea, diarrhoea, vertigo, muscle weakness, and a 'dazed' feeling. These effects often resolve with continued therapy. Fine hand tremors, polyuria, and polydipsia may persist.
  • Adverse effects tend to be directly related to plasma levels and their frequency increases dramatically at levels greater than 1 mmol/L. For more information see the section on Recognizing lithium toxicity.
• Longer-term adverse effects include:
  • Hypothyroidism: there is a small risk that people taking lithium at therapeutic doses may develop clinical goitre, hypothyroidism, or both; the risk appears to be greatest in the first 2 years of treatment. Although this may occur, it should not be a reason for stopping lithium treatment. Levothyroxine replacement is usually indicated. Thyroxine function tests usually return to normal when lithium is discontinued.
  • Hyperthyroidism: lithium-associated thyrotoxicosis is rare and occurs mainly after long-term use. It should not constitute an absolute contraindication to lithium treatment. Specialist advice should be sought regarding management.
  • Hyperparathyroidism: lithium use has been associated with hypercalcaemia accompanied by elevations in circulating parathyroid hormone (PTH). The coexistence of hypercalcaemia and elevated PTH levels suggests primary hyperparathyroidism. However, significantly greater serum levels of calcium are probably required to inhibit PTH secretion during lithium therapy. The presence of mild hypercalcaemia with elevated PTH is consistent with lithium-induced hyperparathyroidism. Parathyroid surgery is not indicated in this situation, and withdrawal of lithium will result in prompt normalization of serum calcium and PTH levels.
  • Nephrotoxicity: a small reduction in glomerular filtration rate is seen in 20% of people taking lithium. In the vast majority of these people this effect is benign. A very small number of people taking lithium may develop interstitial nephritis. Lithium can also cause a reduction in urinary concentrating capacity (nephrogenic diabetes insipidus, with symptoms of thirst and polyuria) which is reversible in the short-to-medium term, but may be irreversible after long-term treatment (greater than 15 years).
  • Renal tumours: cases of microcysts, oncocytomas, and collecting duct renal carcinoma have been reported in people with severe renal impairment who received lithium for more than 10 years.
  • Rhabdomyolysis: muscle weakness and rhabdomyolysis have been reported in people taking lithium.
• The National Patient Safety Agency has developed a lithium patient information booklet. Copies can be obtained from www.nhsforms.co.uk.

[Bocchetta, 2006; BTA, 2006; Taylor, 2021; EMC, 2023d; BNF, 2024]

What are the key drug interactions of lithium?

• Because of lithium's narrow therapeutic index, interactions with other drugs can be very important. The most commonly encountered interactions are with:
  • Diuretics — thiazide diuretics can cause a rapid increase in serum lithium levels (7–10 days) by reducing clearance of lithium. The increase in lithium levels varies from 25–400% Loop diuretics also cause lithium retention but are less likely to result in lithium toxicity.
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) — may increase serum lithium levels. The increase in lithium varies from 40–50%. The mechanism of this interaction is thought to be related to the effects of NSAIDs on fluid balance. This is particularly important if NSAIDs are added to a long-standing prescription of lithium.
  • Haloperidol — severe neurotoxicity has been reported with this combination, however successful and uneventful use of this combination has also been reported.
  • Carbamazepine in combination with lithium has been reported to cause neurotoxic reactions . However successful and uneventful use of this combination has also been reported.
  • Dapagliflozin — concomitant administration with may decrease serum lithium levels due to an increase in lithium renal clearance.  
  • Antidepressants with a serotonergic action (such as selective serotonin reuptake inhibitors, tricyclic antidepressants, venlafaxine, duloxetine) have rarely been linked to an increased incidence of central nervous system toxicity when used with lithium.
  • ACE inhibitors decrease the excretion of lithium. They can also precipitate renal failure. If these two drugs are prescribed together, extra care is required in monitoring both serum creatinine and lithium levels.
  • Drugs that prolong the QT-interval — potential for additive effects when co-administered.
  • Drugs that cause hypokalaemia — potentially increased risk of torsade de points when co-administered.

[Taylor, 2021; EMC, 2023d; BNF, 2024; Preston, 2024]

How should I monitor someone taking lithium?

• Lithium levels are normally measured one week after starting treatment, one week after every dose change, and weekly until the levels are stable. Once levels are stable, levels are usually measured every 3 months.
  • Lithium levels should be measured 10-14 hours post-dose.
• Measure weight or Body Mass Index (BMI), urea and electrolytes estimated glomerular filtration rate (eGFR), calcium and thyroid function tests every 6 months (more often if there is evidence of impaired renal function).
• If the person's urea, or creatinine levels become elevated or if the eGFR declines over two or more tests, consider measuring lithium levels more frequently than 3 monthly. For more information, see the CKS topic on Chronic kidney disease.
• If there is a risk factor for, or existing, cardiovascular disease, an electrocardiogram (ECG) is normally performed before treatment begins.

[NICE, 2023; Taylor, 2021]

How do I recognize lithium toxicity and how should I manage it?

• Signs of lithium toxicity include increasing diarrhoea, vomiting, anorexia, muscle weakness, lethargy, dizziness, ataxia, lack of coordination, tinnitus, blurred vision, coarse tremor of the extremities and lower jaw, muscle hyper-irritability, choreoathetoid movements, dysarthria, and drowsiness.
  • Lithium toxicity occurs at serum lithium concentrations of approximately 1.5 mmol/L and above, but may occur despite an apparently normal plasma level.
  • Severe lithium toxicity occurs at serum lithium concentrations of approximately 2 mmol/L and above.
    • Signs include, hyper-reflexia and hyperextension of limbs, syncope, toxic psychosis, seizures, polyuria, renal failure, electrolyte imbalance, dehydration, circulatory failure, coma, and occasionally death.
  • Mild symptoms may occur at lower levels than full toxicity, but still need rapid assessment.
  • The risk of toxicity is greater in people with hypertension, diabetes, congestive heart failure, chronic renal disease, schizophrenia, or Addison's disease.
  • The National Patient Safety Agency has developed a lithium patient information booklet. Copies can be obtained from www.nhsforms.co.uk.
• If lithium toxicity is suspected, arrange an urgent lithium level immediately and seek specialist advice. Referral to secondary care may be required depending on the severity of symptoms and the certainty of toxicity. Use clinical judgement to determine the urgency of referral.
  • There is no specific antidote to lithium toxicity. In secondary care the treatment is supportive and lithium levels are normally rechecked every 6–12 hours.
  • Osmotic or forced alkaline diuresis may be required, however peritoneal or haemodialysis may be used if levels are above 3 mmol/L.

[Taylor, 2021; BNF, 2024]

What advice should I give to someone taking lithium?

• People taking lithium should be advised:
  • To carry a lithium card.
  • That regular blood tests are important and the results should be recorded in their lithium record booklet.
  • About what adverse effects to expect.
  • How to recognize the symptoms of lithium toxicity.
  • Not to take over-the-counter nonsteroidal anti-inflammatory drugs.
  • That episodes of diarrhoea or vomiting, or any form of dehydration, will lead to sodium depletion and therefore increased plasma lithium levels.
  • To maintain their fluid intake, particularly after sweating (for example, after exercise, in hot climates, or if they have a fever), if they are immobile for long periods, or if they develop a chest infection or pneumonia.
  • That if a dose is missed they should take it as soon as possible; but if yesterday's dose was missed then they should not double today's dose.
  • Not to stop taking lithium abruptly, and that non-compliance may lead to a relapse.
• Women of childbearing age should be advised to use reliable contraception, due to a possible increased risk of birth defects in children exposed in utero.
  • A patient information leaflet on lithium use in pregnancy is available from the UK Teratology Information Service (UKTIS).

[NICE, 2023]

How should I prescribe valproate?

• Valproate is available in the UK in two forms:
  • Semisodium valproate (Depakote^®) is licensed for the treatment of acute mania (but is not licensed for use in children).
  • Sodium valproate (Epilim^®) and valproic acid (Convulex^®) are both unlicensed for the treatment of bipolar disorder.
• Both semisodium and sodium valproate are metabolized to valproic acid, which is responsible for their pharmacological activity.

[BNF, 2024]

What are the contraindications and cautions?

• Prescribe valproate with caution to people with systemic lupus erythematosus.
• Do not prescribe valproate to:
  • Women and girls of childbearing potential, unless there is no suitable alternative (see below). Valproate is a teratogen and can cause physical birth defects and developmental disorders in children exposed in utero.
  • People with:
    • Active liver disease.
    • Personal or family history of severe, drug-related, hepatic dysfunction.
    • Acute porphyria.
    • Mitochondrial disorders caused by mutations in the nuclear gene encoding the mitochondrial enzyme polymerase γ (POLG), for example Alpers-Huttenlocher Syndrome.
• The Medicines and Healthcare Products Regulatory Agency (MHRA) recommends that valproate should not be prescribed to female children and adolescents, women of childbearing potential, or pregnant women unless there is no other effective or tolerated option.
• Females of childbearing potential taking valproate should be enrolled in a pregnancy prevention plan. 
• People under the age of 55 (including males) should only be initiated on valproate if two independent specialists have independently considered and documented that there is no suitable alternative treatment, and males taking valproate and their partners are advised to use effective contraception.
  • There is some data to suggest that valproate use in men around the time of conception might affect neurodevelopment of the child.
  • The MHRA has produced a toolkit  and a number of communication tools to help healthcare professionals advise people about the risks valproate poses to the unborn child. 
  • The UK Teratology Information Service (UKTIS) has produced a patient information leaflet on Valproate in pregnancy
• NICE recommends that if women or young girls of childbearing potential are already taking valproate, they should gradually stop the medicine because of the risk of fetal malformations and adverse neurodevelopmental outcomes after any exposure in pregnancy.

[MHRA, 2022; NICE, 2023; BNF, 2024; EMC, 2024b; MHRA, 2024a; MHRA, 2024b]

What are the adverse effects of valproate?

• Adverse effects of valproate include:
  • Gastric irritation, and hyperammonaemia both of which can lead to intense nausea.
  • Lethargy and confusion. This can occur with starting doses of more than 750 mg a day.
  • Weight gain.
  • Hair loss, with curly regrowth.
  • Peripheral oedema.
  • hyperpigmentation.
  • Very rarely, fulminant hepatic failure.
  • Hyperandrogenism in women. This has been linked to the development of polycystic ovaries.
    • Fertility dysfunctions are in some cases reversible 3 months or more after treatment discontinuation. Limited data suggest strong dose reduction may improve fertility. In some cases, the reversibility of male infertility was unknown.
  • Thrombocytopenia, leucopenia, red cell hypoplasia, and pancreatitis.
  • There is a small risk of suicidal thoughts and behaviour, which may be seen as early as one week after starting treatment. People taking valproate and healthcare professionals should be alert to any mood changes, distressing thoughts, or feelings about suicide or harming themselves at any point during treatment. 
  • Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS).

[MHRA, 2008; Taylor, 2021; BNF, 2024; EMC, 2024b; EMC, 2024c]

What are the key drug interactions of valproate?

• Valproate is highly protein-bound (up to 94%), and other drugs that are also highly protein bound (for example aspirin) may displace valproate from albumin and precipitate toxicity.
• Other less strongly protein-bound drugs (for example warfarin) can be displaced by valproate; this may lead to higher free levels and increased therapeutic effect or toxicity of the concomitant drug.
• Valproate is metabolized by the liver, so drugs that inhibit cytochrome P450 enzymes (for example erythromycin, fluoxetine, and cimetidine) can increase valproate levels.
• Valproate can increase the plasma levels of some drugs, possibly by inhibition of their metabolism (for example tricyclic antidepressants, particularly clomipramine).
• Nimodipine — the levels of this drug can be increased when taken with valproate. A dose reduction of nimodipine should be made is a person suffers hypotension.
• Lamotrigine — valproate increases the exposure to lamotrigine. Manufacturer advises adjust lamotrigine dose and monitor for rash.
• Carbapenem antibiotics (such as panipenem, imipenem and meropenem) — decreases in blood levels of valproic acid have been reported during co-administration with carbapenem antibiotics leading to a 60% – 100% decrease in valproic acid levels within two days. Co-administration should therefore be avoided. If treatment with these antibiotics cannot be avoided close monitoring of valproic acid blood levels should be performed.
• Quetiapine — co-administration may increase the risk of neutropenia/leucopenia.

[Taylor, 2021; BNF, 2024; EMC, 2024b]

How should I monitor someone taking valproate?

• Before starting treatment, a full blood count, baseline liver function tests (LFTs), and body weight or body mass index (BMI) are usually measured.
• Ensure that LFTs, BMI, and a full blood count are measured 6 months after treatment has been initiated, and every 12 months thereafter.
• Valproate levels are not routinely measured unless there is evidence of ineffectiveness, poor compliance, or toxicity is suspected.

[NICE, 2023; BNF, 2024]

What advice should I give to someone taking valproate?

• Advise the person and their carers how to recognize the signs and symptoms of:
  • Blood disorders (for example any unexplained bleeding, bruising, purpura, sore throat, fever, or malaise that occurs during treatment).
  • Liver disorders (for example sudden onset of weakness, malaise, anorexia, lethargy, oedema, and drowsiness [which are sometimes associated with repeated vomiting and abdominal pain], and jaundice).
  • Pancreatitis (for example abdominal pain, nausea, and vomiting).
• Inform them that they should seek immediate medical help if these develop.

[BNF, 2024]