Mood stabilizers

TREATMENT STRATEGIES AND PSYCHOPHARMACOLOGY

Mood stabilizers

Key points

Georgina Boon

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Because of its high teratogenicity, do not use valproate in women of childbearing potential unless alternative treatments are ineffective or not tolerated

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Wherever possible, avoid lithium, lamotrigine and carbamazepine in women of childbearing potential because of the potential teratogenic properties

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Always check for drug interactions with other medicines, especially if using carbamazepine

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Check adherence and plasma concentrations if the response is poor

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Advise patients on lamotrigine to see a doctor urgently if a rash develops

Abstract Mood stabilizers include lithium, carbamazepine, lamotrigine and valproate. Some antipsychotics are also mood-stabilizing in patients with bipolar disorder. This article gives advice on the appropriate dosing of mood stabilizers, their use in vulnerable groups of patients, and how and when to monitor therapeutic plasma drug concentrations. Important adverse effects and common drug interactions are also included.

Keywords Antipsychotics; carbamazepine; lamotrigine; lithium; sodium valproate; valproate; valproic acid

Use of mood stabilizers

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Mood stabilizers are used in the management of patients with bipolar affective disorder and schizoaffective disorder to reduce the frequency of manic, hypomanic and depressive episodes. Before starting a mood stabilizer, baseline blood tests are required, as well as electrocardiography if there is pre-existing cardiovascular disease. The dose should be titrated according to plasma drug concentrations, particularly for lithium but also for valproate. National Institute for Health and Care Excellence (NICE) guidance for bipolar disorder was published in September 2014,1 and British Association of Psychopharmacology (BAP) guidelines for treating bipolar disorder in March 2016.2 Treatment options vary depending on the presenting phase of the illness and existing antimanic medication (if any). In acute mania, if patients are not already taking a mood stabilizer, single-agent therapy with an antipsychotic (olanzapine, risperidone, haloperidol, quetiapine) is recommended.3 If a patient is on a mood stabilizer, adding an antipsychotic is more effective than using a mood stabilizer alone. In acute bipolar depression, olanzapine with fluoxetine or quetiapine monotherapy are first-line options. Longer term treatment must take into account what has been beneficial in the acute treatment phase. Lithium has the strongest evidence base (whether mania or depression predominates) and is also associated with a reduced risk of suicide. For prevention of depressive episodes, quetiapine or lamotrigine is also beneficial, and for prevention of mania combination therapy of lithium with an antipsychotic or valproate is a further option.4 If combinations of prophylactic agents are ineffective, carbamazepine can also be considered, although evidence for this is less robust. Mood stabilizers should not be stopped abruptly as this can increase the risk of relapse; they should be gradually reduced over 4 weeks.5 For women of childbearing potential, it is advised that

valproate, lithium, lamotrigine and carbamazepine are avoided because of their potential teratogenic properties. If they are prescribed, adequate contraception should be offered and prophylactic folic acid (5 mg daily) prescribed. See Table 1 for important adverse effects and interactions of mood stabilizers and Box 1 for use of mood stabilizers in vulnerable groups. Lithium Lithium acts upon various brain neurotransmitter systems. Through its effects on glycogen synthase kinase-3b and reduction of protein kinase C, lithium can cause neuroplastic changes within the brain that are associated with mood stabilization. Different lithium salts are available and preparations vary in bioavailability, so it should always be prescribed by brand. Lithium has a narrow therapeutic index and most toxic effects are dose-related. Continuing essential monitoring includes measurement of serum lithium concentration every 3 months and thyroid function tests, serum urea and electrolytes and serum calcium/parathyroid hormone every 6 months. The target range for serum lithium is 0.6e0.8 mmol/litre (aim for 0.8e1.0 mmol/litre if the patient has previously relapsed while taking lithium or is currently symptomatic). Valproate Valproate has multiple actions: it has effects on glycogen synthase kinase-3b to aid mood stabilization, increases g-aminobutyric acid and reduces protein kinase C concentrations. It may also deplete inositol. Valproate is available as sodium valproate, valproic acid and semi-sodium valproate (a 1:1 molar combination of sodium valproate and valproic acid). Most clinical studies have used semi-sodium valproate, although the therapeutic differences between sodium valproate and semi-sodium valproate have not been established. Continuing essential monitoring includes liver function tests, full blood count and weight every

Georgina Boon MPharm DipGPP MFRPSII is a Highly Specialist Pharmacist at Bethlem Royal Hospital Pharmacy Department, Bethlem Royal Hospital, Beckenham, Kent, UK. Competing interests: none declared.

MEDICINE 44:12

Do not stop mood stabilizers abruptly e they should be discontinued over 4 weeks

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MEDICINE 44:12

Mood stabilizers in vulnerable groups

Pregnancy C

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Always discuss the risks of treating and not treating with mood stabilizers during pregnancy Avoid valproate and carbamazepine in pregnancy (neural tube defects). If prescribed for women of childbearing age, offer adequate contraception and prescribe prophylactic folic acid (5 mg daily) Try to avoid lamotrigine (cleft palate) and lithium (Ebstein’s anomaly), but the risk is lower than with valproate and carbamazepine If possible, stop lithium and consider restarting it in the second trimester If a woman remains on lithium, check the serum concentration every 4 weeks and ensure adequate fluid intake

Elderly patients C

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Use lower doses of mood stabilizers and antipsychotics for all phases of treatment where recommended (check the British National Formulary and Summaries of Product Characteristics for prescribing recommendations in the elderly) Consider the negative impact that drugs with anticholinergic activity (e.g. quetiapine, olanzapine, haloperidol, risperidone, asenapine) can have on cognitive function and mobility Take into account the increased risk of drug interactions in elderly patients Ensure that medical co-morbidities have been recognized and treated

Hepatic impairment C

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Valproate can cause liver dysfunction so should be avoided in patients with severe hepatic impairment No adjustment of lithium is needed in hepatic impairment

Renal impairment C

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Lithium is potentially nephrotoxic and should where possible be avoided in renal impairment Valproate can be used in renal impairment, but start at lower doses in cases of severe impairment and titrate according to response

Box 1

6 months. The suggested target range for plasma concentrations for mood stabilization is 50e100 mg/litre. Carbamazepine Carbamazepine blocks voltage-dependent sodium channels, inhibiting repetitive neuronal firing. It decreases glutamate release and decreases the turnover of noradrenaline (norepinephrine) and dopamine. NICE considers carbamazepine to be a third-line prophylactic agent. Although there is evidence for its

Table 1

ACE, angiotensin-converting enzyme; NSAIDs, non-steroidal anti-inflammatory drugs; SSRIs, selective serotonin reuptake inhibitors. a Consult Martindale and Stockley’s (both available at www.medicinescomplete.com) for a comprehensive list of all adverse effects and interactions.

Increases risperidone concentration. Lamotrigine concentration is increased by valproate e adjust starting doses Nausea, diarrhoea, dry mouth, headache, drowsiness, rash e patients must be advised to report any rashes Lamotrigine

Potent enzyme inducer with many significant interactions; affects phenytoin, benzodiazepines and many antipsychotics and antibiotics Dry mouth, nausea, headache, drowsiness, dizziness, diplopia, blood disorders e patients must be counselled on how to recognize signs Carbamazepine

Some enzyme inhibition, increases concentrations of lamotrigine Drowsiness, nausea, diarrhoea, weight gain, transient hair loss Valproate

Avoid NSAIDs, ACE inhibitors and thiazide diuretics. If these must be prescribed, reduce the lithium dose by 25e50% and monitor the patient closely for adverse effects. Also with SSRIs and methyldopa Nausea, vomiting, fine tremor, renal impairment, weight gain Lithium

Important adverse effects Drug name

Important adverse effects and drug interactionsa

Common interactions

TREATMENT STRATEGIES AND PSYCHOPHARMACOLOGY

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TREATMENT STRATEGIES AND PSYCHOPHARMACOLOGY

use as a mood stabilizer, it is not particularly well tolerated. Carbamazepine is a potent inducer of hepatic cytochrome enzymes and is metabolized by CYP3A4, so there is potential for interaction with other medications. Continuing essential monitoring includes liver function tests, full blood count, serum concentration and weight every 6 months. The target range for serum carbamazepine is 7e12 mg/litre.

important to note that different maximum licensed doses apply according to indication, so it is advisable to consult the British National Formulary (BNF) and latest Summaries of Product Characteristics (SPC) (available at www.medicines.org.uk) for full licensing information. A

Lamotrigine The mood stabilization effect of lamotrigine is related to inhibition of sodium and calcium channels in presynaptic neurones and subsequent stabilization of the neuronal membrane. Lamotrigine has been shown to be effective as a mood stabilizer, particularly where depression predominates. Dosage recommendations must be adhered to closely to reduce the risk of rash, but the need for slow titration may limit clinical use. Patients taking lamotrigine should be advised to see a doctor urgently if a rash develops as there is a risk of serious skin reactions, including StevenseJohnson syndrome. No other specific monitoring is required with lamotrigine. The target range for serum lamotrigine is 2.5e15 mg/litre.

KEY REFERENCES 1 National Institute for Health and Care Excellence. Bipolar disorder: assessment and management. Clinical Guideline No 185. 2014, updated February 2016. https://www.nice.org.uk/guidance/cg185 (accessed 14 May 2016). 2 Goodwin GM, Haddad PM, Ferrier IN, et al. Evidence-based guidelines for treating bipolar disorder: revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2016; 30: 495e553. 3 Cipriani A, Barbui C, Salanti G, et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multipletreatments meta-analysis. Lancet 2011; 378: 1306e15. 4 Geddes J, Goodwin G, Rendell J, et al. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar 1 disorder (BALANCE). Lancet 2010; 375: 385e95. 5 Taylor D, Paton C, Kapur S. The Maudsley prescribing guidelines in psychiatry. 12th edn. Chichester, UK: Wiley-Blackwell, 2015.

Antipsychotics as mood stabilizers Individual antipsychotics variously possess sedative, anxiolytic, antimanic and mood-stabilizing properties. Certain antipsychotics (olanzapine, risperidone, quetiapine, haloperidol, aripiprazole, asenapine) have a UK licence for use in mania. It is

TEST YOURSELF To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the end of the issue or online here.

Question 1

B. C. D. E.

A 29-year-old woman presented with symptoms of mania. Which medication would be least likely to pose a risk to the fetus if she became pregnant? A. Carbamazepine B. Lamotrigine C. Lithium D. Olanzapine E. Sodium valproate

Question 3 A 50-year-old woman presented with a 4-month history of weakness, cold intolerance, constipation and weight gain. She had been treated with lithium for bipolar depression for more than 10 years. On examination, her pulse was 67 bpm, her blood pressure 128/ 86 mmHg and her temperature 36.0 C. She had dry, coarse skin and swelling of the hands and feet.

Question 2 A 42-year-old man presented with a 2-month history of tremor affecting his hands and finding it harder to play the guitar, which was one of his favourite pastimes. He had bipolar disorder that had been difficult to control, and he had required several medication changes in the previous 18 months to control manic episodes. However, his mood had been stable on his current regimen.

Which of the following blood tests will confirm the most likely diagnosis? A. Electrolyte levels B. Lithium level C. Liver function tests D. Thyroid function tests E. Oestrogen levels

Which of the following medications is the most likely cause of his tremor? A. Carbamazepine

MEDICINE 44:12

Lamotrigine Lithium Olanzapine Sodium valproate

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