Lithium

Mechanism of action

Lithium is an element that the body handles in a similar way to sodium. The ubiquitous nature of sodium in the human body, its involvement in a wide range of biological processes, and the potential for lithium to alter these processes, has made it extremely difficult to ascertain the key mechanism(s) of action of lithium in regulating mood. For example, there is some evidence that people with bipolar illness have higher intracellular concentrations of sodium and calcium than controls, and that lithium can reduce these. Reduced activity of sodium-dependent intracellular second messenger systems has been demonstrated, as have modulation of dopamine and serotonin neurotransmitter pathways, reduced activity of protein kinase C and reduced turnover of arachidonic acid. Lithium may also have neuroprotective effects, possibly mediated through its effects on N-methyl-D-aspartate (NMDA) pathways. For a review see Marmol (2008).¹ It is notable that, with the exception of a database study linking lithium use with a reduced risk of developing dementia,² literature pertaining to the possible neuroprotective effect of lithium reports largely on either in vitro or animal studies. The clinical literature is rather more dominated by reports of neurotoxicity.³

Indications

Lithium is effective in the treatment of moderate to severe mania with a number needed to treat (NNT) of 6.⁴ Its use for this indication is limited by the fact that it usually takes at least a week to achieve a response⁵ and that the co-administration of antipsychotics may increase the risk of neurological side-effects. It can also be difficult to achieve therapeutic plasma levels rapidly and monitoring can be problematic if the patient is uncooperative.

The main indication for lithium is in the prophylaxis of bipolar affective disorder where it reduces both the number and the severity of relapses.⁶ Lithium is more effective at preventing manic than depressive relapse;⁷ the NNT to prevent relapse into mania or depression has been calculated to be 10 and 14 respectively.⁷ Lithium also offers some protection against antidepressant-induced hypomania. It is generally clinically appropriate to initiate prophylactic treatment: (1) after a single manic episode that was associated with significant risk and adverse consequences; (2) in the case of bipolar I illness, two or more acute episodes; or (3) in the case of bipolar II illness, significant functional impairment, frequent episodes or significant risk of suicide.⁸ NICE supports the use of lithium as a first-line mood stabiliser; lithium alone is probably more effective than valproate alone,⁹ with the combination being better still.¹⁰ The earlier in the course of the illness that lithium treatment is started, the better the response is likely to be.¹¹

Lithium augmentation of an antidepressant in patients with unipolar depression is recommended by NICE as a next-step treatment in patients who have not responded to standard antidepressant drugs.¹² A recent meta-analysis found lithium to be three times as effective as placebo for this indication with a NNT of 5,¹³ although the response rate in STAR-D was more modest (see section on 'Refractory depression' in Chapter 4).

The effectiveness of lithium in treating mood disorders does not go unchallenged. For a review, see Moncrieff.¹⁴

Lithium is also used to treat aggressive¹⁵ and self-mutilating behaviour, to both prevent and treat steroid-induced psychosis,¹⁶ and to raise the white blood cell count in patients receiving clozapine.

Lithium and suicide

It is estimated that 15% of people with bipolar affective disorder take their own life.¹⁷ A meta-analysis of clinical trials concluded that lithium reduced by 80% the risk of both attempted and completed suicide in patients with bipolar illness,^18,19 and two large database studies have shown that lithium-treated patients were less likely to complete suicide than patients treated with divalproex²⁰ or with other mood stabilising drugs (valproate, gabapentin, carbamazepine).²¹

In patients with unipolar depression, lithium also seems to protect against suicide; the effect size being slightly smaller than that seen in bipolar illness.^19,22 The mechanism of this protective effect is unknown.

Plasma levels

A recent systematic review of the relationship between plasma levels and response in patients with bipolar illness concluded that the minimum effective plasma level for prophylaxis is 0.4 mmol/L, with the optimal range being 0.6–0.75 mmol/L. Levels above 0.75 mmol/L offer additional protection only against manic symptoms.^8,23 Changes in plasma levels seem to worsen the risk of relapse.²⁴ The optimal plasma level range in patients who have unipolar depression is less clear.¹³

Children and adolescents may require higher plasma levels than adults to ensure that an adequate concentration of lithium is present in the central nervous system (CNS).²⁵

Lithium is rapidly absorbed from the gastrointestinal tract but has a long distribution phase. Blood samples for plasma lithium level estimations should be taken 10–14 hours (ideally 12) post dose in patients who are prescribed a single daily dose of a prolongedrelease preparation at bedtime.²⁶

Formulations

There is no clinically significant difference in the pharmacokinetics of the two most widely prescribed brands of lithium in the UK: Priadel and Camcolit. Other preparations should not be assumed to be bioequivalent and should be prescribed by brand.

• Lithium carbonate 400 mg tablets each contain 10.8 mmol/lithium.
• Lithium citrate liquid is available in two strengths and should be administered twice daily:
• 5.4 mmol/5mLs is equivalent to 200 mg lithium carbonate
• 10.8 mmol/5mLs is equivalent to 400 mg lithium carbonate.

Lack of clarity over which liquid preparation is intended when prescribing can lead to the patient receiving a sub-therapeutic or toxic dose.

Adverse effects

Most side-effects are dose- (and therefore plasma level) related. These include mild gastro-intestinal upset, fine tremor, polyuria and polydipsia. Polyuria may occur more frequently with twice-daily dosing.²⁷ Propranolol can be useful in lithium-induced tremor. Some skin conditions such as psoriasis and acne can be aggravated by lithium therapy. Lithium can also cause a metallic taste in the mouth, ankle oedema and weight gain.

Lithium can cause a reduction in urinary concentrating capacity—nephrogenic diabetes insipidus—hence the occurrence of thirst and polyuria. This effect is usually reversible in the short to medium term but may be irreversible after long-term treatment (> 15 years).^26,27 Lithium treatment can also lead to a reduction in the glomerular filtration rate (GFR);²⁸ the magnitude of the risk is uncertain.^29,30 One large cross-sectional study found that one-third of young people prescribed lithium had an e-GFR of < 60 mLs/ minute (chronic kidney disease stage 3).²⁸ A very small number of patients may develop interstitial nephritis. Lithium levels of > 0.8 mmol/L are associated with a higher risk of renal toxicity.²³

In the longer term, lithium increases the risk of hypothyroidism;³¹ in middle-aged women, the risk may be up to 20%.³² A case has been made for testing thyroid autoantibodies in this group before starting lithium (to better estimate risk) and for measuring thyroid function tests (TFTs) more frequently in the first year of treatment.³³ Hypothyroidism is easily treated with thyroxine. TFTs usually return to normal when lithium is discontinued. Lithium also increases the risk of hyperparathyroidism, and some recommend that calcium levels should be monitored in patients on long-term treatment.³³ Clinical consequences of chronically increased serum calcium include renal stones, osteoporosis, dyspepsia, hypertension and renal impairment.³³

For a review of the toxicity profile of lithium, see McKnight et al.³⁴

Lithium toxicity

Toxic effects reliably occur at levels > 1.5 mmol/L and usually consist of gastro-intestinal effects (increasing anorexia, nausea and diarrhoea) and CNS effects (muscle weakness, drowsiness, ataxia, course tremor and muscle twitching). Above 2 mmol/L, increased disorientation and seizures usually occur, which can progress to coma, and ultimately death. In the presence of more severe symptoms, osmotic or forced alkaline diuresis should be used (note NEVER thiazide or loop diuretics). Above 3 mmol/L peritoneal or haemodialysis is often used. These plasma levels are only a guide and individuals vary in their susceptibility to symptoms of toxicity.

Most risk factors for toxicity involve changes in sodium levels or the way the body handles sodium. For example low salt diets, dehydration, drug interactions (see Table 3.1) and some uncommon physical illnesses such as Addison's disease.

Information relating to the symptoms of toxicity and the common risk factors should always be given to patients when treatment with lithium is initiated.³⁵ This information should be repeated at appropriate intervals to make sure that it is clearly understood.

Pre-treatment tests

Before prescribing lithium, renal, thyroid and cardiac function should be checked. As a minimum, e-GRF³⁶ and TFTs should be checked. An electrocardiogram (ECG) is also recommended in patients who have risk factors for, or existing, cardiovascular disease. A baseline measure of weight is also desirable.

Lithium is a human teratogen. Women of child-bearing age should be advised to use a reliable form of contraception. See section on 'Pregnancy' in Chapter 7.

Table 3.1 Lithium: prescribing and monitoring

On-treatment monitoring⁸

NICE recommend that plasma lithium, e-GFR and TFTs should be checked every 6 months. More frequent tests may be required in those who are prescribed interacting drugs, elderly or have established chronic kidney disease (CKD). A patient safety alert related to the importance of biochemical monitoring in patients prescribed lithium has been issued by the National Patient Safety Agency.³⁷ Weight (or BMI) should also be monitored. Lithium monitoring in clinical practice in the UK is known to be suboptimal,³⁸ although there has been a modest improvement over time.³⁹ The use of automated reminder systems has been shown to improve monitoring rates.⁴⁰

Discontinuation

Intermittent treatment with lithium may worsen the natural course of bipolar illness. A much greater than expected incidence of manic relapse is seen in the first few months after discontinuing lithium,⁴¹ even in patients who have been symptom free for as long as 5 years.⁴² This has led to recommendations that lithium treatment should not be started unless there is a clear intention to continue it for at least 3 years.⁴³ This advice has obvious implications for initiating lithium treatment against a patient's will (or in a patient known to be non-compliant with medication) during a period of acute illness.

The risk of relapse is reduced by decreasing the dose gradually over a period of at least a month,⁴⁴ and avoiding decremental serum level reductions of > 0.2 mmol/L.²³ The course of illness may, however, still be adversely affected: a recent naturalistic study found that, in patients who had been in remission for at least 2 years and had discontinued lithium very slowly, the recurrence rate was at least three times greater than in patients who continued lithium; significant survival differences persisted for many years. Patients maintained on high lithium levels prior to discontinuation were particularly prone to relapse.⁴⁵

One large US study based on prescription records found that half of those prescribed lithium took almost all of their prescribed doses, a quarter took between 50 and 80%, and the remaining quarter took less than 50%. In addition one-third of patients took lithium for less than 6 months in total.⁴⁶ A large audit found that one in ten patients prescribed long-term lithium treatment had a plasma level below the therapeutic range.⁴⁷ It is clear that sub-optimal adherence limits the effectiveness of lithium in clinical practice. One database study suggested the extent to which lithium was taken was directly related to the risk of suicide (more prescriptions= lower suicide rate).⁴⁸

Less convincing data support the emergence of depressive symptoms in patients with bipolar illness after lithium discontinuation.⁴¹ There are few data relating to patients with unipolar depression.

Interactions with other drugs^49,50

Because of lithium's relatively narrow therapeutic index, pharmacokinetic interactions with other drugs can precipitate lithium toxicity. Most clinically significant interactions are with drugs that alter renal sodium handling; see Table 3.2.

Table 3.2 Lithium: clinically relevant drug interactions

Angiotensin converting enzyme inhibitors

Angiotensin converting enzyme (ACE) inhibitors can (1) reduce thirst which can lead to mild dehydration, and (2) increase renal sodium loss leading to increased sodium re-absorption by the kidney, resulting in an increase in lithium plasma levels. The magnitude of this effect is variable; from no increase to a four-fold increase. The full effect can take several weeks to develop. The risk seems to be increased in patients with heart failure, dehydration and renal impairment (presumably because of changes in fluid balance/handling). In the elderly, ACE inhibitors increase seven-fold the risk of hospitalisation due to lithium toxicity. ACE inhibitors can also precipitate renal failure so, if co-prescribed with lithium, more frequent monitoring of e-GFR and plasma lithium is required.

The following drugs are ACE inhibitors: captopril, cilazapril enalapril, fosinopril, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril and trandolapril.

Care is also required with angiotensin II receptor antagonists; candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan and valsartan.

Diuretics

Diuretics can reduce the renal clearance of lithium, the magnitude of this effect being greater with thiazide than loop diuretics. Lithium levels usually rise within 10 days of a thiazide diuretic being prescribed; the magnitude of the rise is unpredictable and can vary from an increase of 25% to 400%.

The following drugs are thiazide (or related) diuretics: bendroflumethiazide, chlortalidone, cyclopenthiazide, indapamide, metolazone and xipamide.

Although there are case reports of lithium toxicity induced by loop diuretics, many patients receive this combination of drugs without apparent problems. The risk of an interaction seems to be greatest in the first month after the loop diuretic has been prescribed and extra lithium plasma level monitoring during this time is recommended if these drugs are co-prescribed. Loop diuretics can increase sodium loss and subsequent re-absorption by the kidney. Patients taking loop diuretics may also have been advised to restrict their salt intake; this may contribute to the risk of lithium toxicity in these individuals.

The following drugs are loop diuretics: bumetanide, furosemide and torasemide.

Non-steroidal anti-inflammatory drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the synthesis of renal prostaglandins, thereby reducing renal blood flow and possibly increasing renal re-absorption of sodium and therefore lithium. The magnitude of the rise is unpredictable for any given patient; case reports vary from increases of around 10% to over 400%. The onset of effect also seems to be variable; from a few days to several months. Risk appears to be increased in those patients who have impaired renal function, renal artery stenosis or heart failure and who are dehydrated or on a low salt diet. There are a growing number of case reports of an interaction between lithium and cyclo-oxygenase (COX)-2 inhibitors.

NSAIDs (or COX-2 inhibitors) can be combined with lithium, but (1) they should be prescribed regularly NOT prn, and (2) more frequent plasma lithium monitoring is essential.

Some NSAIDs can be purchased without a prescription, so it is particularly important that patients are aware of the potential for interaction.

The following drugs are NSAIDs or COX-2 inhibitors: aceclofenac, acemetacin, celecoxib, dexibuprofen, dexketofrofen, diclofenac, diflunisal, etodolac, etoricoxib, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, lumiracoxib, mefenamic acid, meloxicam, nabumetone, naproxen, piroxicam, sulindac, tenoxicam and tiaprofenic acid.

Carbamazepine

There are rare reports of neurotoxicity when carbamazepine is combined with lithium. Most are old and in the context of treatment involving high plasma lithium levels. It is of note though that carbamazepine can cause hyponatraemia, which may in turn lead to lithium retention and toxicity. Similarly, rare reports of CNS toxicity implicate selective serotonin reuptake inhibitors (SSRIs), another group of drugs that can cause hyponatraemia.

References

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2. Kessing LV et al. Does lithium protect against dementia? Bipolar Disord 2010; 12:87–94.
3. Fountoulakis KN et al. A systematic review of existing data on long-term lithium therapy: neuroprotective or neurotoxic? Int J Neuropsychopharmacol 2008; 11:269–287.
4. Storosum JG et al. Magnitude of effect of lithium in short-term efficacy studies of moderate to severe manic episode. Bipolar Disord 2007; 9:793–798.
5. Ferrier IN et al. Lithium therapy. Adv Psychiatr Treat 1995; 1:102–110.
6. Tondo L et al. Long-term clinical effectiveness of lithium maintenance treatment in types I and II bipolar disorders. Br J Psychiatry Suppl 2001; 41:s184–s190.
7. Geddes JR et al. Long-term lithium therapy for bipolar disorder: systematic review and meta-analysis of randomized controlled trials. Am J Psychiatry 2004; 161:217–222.
8. National Institute for Health and Care Excellence. Bipolar disorder: the assessment and management of bipolar disorder in adults, children and young people in primary and secondary care. Draft for consultation, April 2014. http://www.nice.org.uk/
9. Kessing LV et al. Valproate v. lithium in the treatment of bipolar disorder in clinical practice: observational nationwide register-based cohort study. Br J Psychiatry 2011; 199:57–63.
10. Geddes JR et al. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet 2010; 375:385–395.
11. Kessing LV et al. Starting lithium prophylaxis early v. late in bipolar disorder. Br J Psychiatry 2014; 205:214–220.
12. National Institute for Health and Clinical Excellence. Depression in adults: The treatment and management of depression in adults. Clinical Guideline 90, 2009. http://www.nice.org.uk/Guidance/cg90
13. Crossley NA et al. Acceleration and augmentation of antidepressants with lithium for depressive disorders: two meta-analyses of randomized, placebo-controlled trials. J Clin Psychiatry 2007; 68:935–940.
14. Moncrieff J. Lithium: evidence reconsidered. Br J Psychiatry 1997; 171:113–119.
15. Tyrer SP. Lithium and treatment of aggressive behaviour. Eur Neuropsychopharmacol 1994; 4:234–236.
16. Falk WE et al. Lithium prophylaxis of corticotropin-induced psychosis. JAMA 1979; 241:1011–1012.
17. Harris EC et al. Excess mortality of mental disorder. Br J Psychiatry 1998; 173:11–53.
18. Baldessarini RJ et al. Decreased risk of suicides and attempts during long-term lithium treatment: a meta-analytic review. Bipolar Disord 2006; 8:625–639.
19. Cipriani A et al. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ 2013; 346:f3646.
20. Goodwin FK et al. Suicide risk in bipolar disorder during treatment with lithium and divalproex. JAMA 2003; 290:1467–1473.
21. Collins JC et al. Divalproex, lithium and suicide among Medicaid patients with bipolar disorder. J Affect Disord 2008; 107:23–28.
22. Guzzetta F et al. Lithium treatment reduces suicide risk in recurrent major depressive disorder. J Clin Psychiatry 2007; 68:380–383.
23. Severus WE et al. What is the optimal serum lithium level in the long-term treatment of bipolar disorder–a review? Bipolar Disord 2008; 10:231–237.
24. Perlis RH et al. Effect of abrupt change from standard to low serum levels of lithium: a reanalysis of double-blind lithium maintenance data. Am J Psychiatry 2002; 159:1155–1159.
25. Moore CM et al. Brain-to-serum lithium ratio and age: an in vivo magnetic resonance spectroscopy study. Am J Psychiatry 2002; 159:1240–1242.
26. Anon. Using lithium safely. Drug Ther Bull 1999; 37:22–24.
27. Bowen RC et al. Less frequent lithium administration and lower urine volume. Am J Psychiatry 1991; 148:189–192.
28. Bassilios N et al. Monitoring of glomerular filtration rate in lithium-treated outpatients–an ambulatory laboratory database surveillance. Nephrol Dial Transplant 2008; 23:562–565.
29. Paul R et al. Meta-analysis of the effects of lithium usage on serum creatinine levels. J Psychopharmacol 2010; 24:1425–1431.
30. Kripalani M et al. Lithium and chronic kidney disease. BMJ 2009; 339:b2452.
31. Frye MA et al. Depressive relapse during lithium treatment associated with increased serum thyroid-stimulating hormone: results from two placebo-controlled bipolar I maintenance studies. Acta Psychiatr Scand 2009; 120:10–13.
32. Johnston AM et al. Lithium-associated clinical hypothyroidism. Prevalence and risk factors. Br J Psychiatry 1999; 175:336–339.
33. Livingstone C et al. Lithium: a review of its metabolic adverse effects. J Psychopharmacol 2006; 20:347–355.
34. McKnight RF et al. Lithium toxicity profile: a systematic review and meta-analysis. Lancet 2012; 379:721–728.
35. Gerrett D et al. Prescribing and monitoring lithium therapy: summary of a safety report from the National Patient Safety Agency. BMJ 2010; 341:c6258.
36. Morriss R et al. Lithium and eGFR: a new routinely available tool for the prevention of chronic kidney disease. Br J Psychiatry 2008; 193:93–95.
37. National Patient Safety Agency. Safer lithium therapy. NPSA/2009/PSA005. 2009. http://www.nrls.npsa.nhs.uk/
38. Collins N et al. Standards of lithium monitoring in mental health trusts in the UK. BMC Psych 2010; 10:80.
39. Paton C et al. Monitoring lithium therapy: the impact of a quality improvement programme in the UK. Bipolar Disord 2013; 15:865–875.
40. Kirkham E et al. Impact of active monitoring on lithium management in Norfolk. Ther Adv Psychopharmacol 2013; 3:260–265.
41. Cavanagh J et al. Relapse into mania or depression following lithium discontinuation: a 7-year follow-up. Acta Psychiatr Scand 2004; 109:91–95.
42. Yazici O et al. Controlled lithium discontinuation in bipolar patients with good response to long-term lithium prophylaxis. J Affect Disord 2004; 80:269–271.
43. Goodwin GM. Recurrence of mania after lithium withdrawal. Implications for the use of lithium in the treatment of bipolar affective disorder. Br J Psychiatry 1994; 164:149–152.
44. Baldessarini RJ et al. Effects of the rate of discontinuing lithium maintenance treatment in bipolar disorders. J Clin Psychiatry 1996; 57:441–448.
45. Biel MG et al. Continuation versus discontinuation of lithium in recurrent bipolar illness: a naturalistic study. Bipolar Disord 2007; 9:435–442.
46. Sajatovic M et al. Treatment adherence with lithium and anticonvulsant medications among patients with bipolar disorder. Psychiatr Serv 2007; 58:855–863.
47. Paton C et al. Lithium in bipolar and other affective disorders: prescribing practice in the UK. J Psychopharmacol 2010; 24:1739–1746.
48. Kessing LV et al. Suicide risk in patients treated with lithium. Arch Gen Psychiatry 2005; 62:860–866.
49. Stockley's Drug Interactions. London: Pharamceutical Press; 2014. https://www.medicinescomplete.com/
50. Juurlink DN et al. Drug-induced lithium toxicity in the elderly: a population-based study. J Am Geriatr Soc 2004; 52:794–798.

Valproate

Mechanism of action¹

Valproate is a simple branched-chain fatty acid. Its mechanism of action is complex and not fully understood. Valproate inhibits the catabolism of gamma-aminobutyric acid (GABA), reduces the turnover of arachidonic acid, activates the extracellular signalregulated kinase (ERK) pathway thus altering synaptic plasticity, interferes with intracellular signaling, promotes brain-derived neurotrophic factor (BDNF) expression and reduces levels of protein kinase C. Recent research has focused on the ability of valproate to alter the expression of multiple genes that are involved in transcription regulation, cytoskeletal modifications and ion homeostasis. Other mechanisms that have been proposed include depletion of inositol, and indirect effects on non-GABA pathways through inhibition of voltage-gated sodium channels.

There is a growing literature relating to the potential use of valproate as an adjunctive treatment in several types of cancer; the relevant mechanism of action being inhibition of histone deacetylase.^2–4

Formulations

Valproate is available in the UK in three forms: sodium valproate and valproic acid (licensed for the treatment of epilepsy), and semi-sodium valproate, licensed for the treatment of acute mania. Both semi-sodium and sodium valproate are metabolised to valproic acid, which is responsible for the pharmacological activity of all three preparations.⁵ Clinical studies of the treatment of affective disorders variably use sodium valproate, semi-sodium valproate, 'valproate' or valproic acid. The great majority have used semi-sodium valproate (divalproex in the US).

In the US, valproic acid is widely used in the treatment of bipolar illness,⁶ and in the UK sodium valproate is widely used. It is important to remember that doses of sodium valproate and semi-sodium valproate are not equivalent; a slightly higher (approximately 10%) dose is required if sodium valproate is used to allow for the extra sodium content.

It is unclear if there is any difference in efficacy between valproic acid, valproate semi-sodium and sodium valproate. One large US quasi-experimental study found that inpatients who initially received the semi-sodium preparation had a hospital stay that was a third longer than patients who initially received valproic acid.⁷ Note that sodium valproate controlled release (Epilim Chrono) can be administered as a once-daily dose whereas other sodium and semi-sodium valproate preparations require at least twicedaily administration.

Indications

Randomised controlled trials (RCTs) have shown valproate to be effective in the treatment of mania,^8,9 with a response rate of 50% and a NNT of 2–4,¹⁰ although large negative studies do exist.¹¹ One RCT found lithium to be more effective overall than valproate⁹ but a large (n = 300) randomized open trial of 12 weeks duration found lithium and valproate to be equally effective in the treatment of acute mania.¹² Valproate may be effective in patients who have failed to respond to lithium; in a small placebo controlled RCT (n = 36) in patients who had failed to respond to or could not tolerate lithium, the median decrease in Young Mania Rating Scale scores was 54% in the valproate group and 5% in the placebo group.¹³ It may be less effective than olanzapine, both as monotherapy¹⁴ as an adjunctive treatment to lithium¹² in acute mania. A network meta-analysis reported that valproate was less effective but better tolerated than lithium.¹⁵

A meta-analysis of four small RCTs concluded that valproate is effective in bipolar depression with a small to medium effect size,¹⁶ although further data are required.¹⁰

Although open label studies suggest that valproate is effective in the prophylaxis of bipolar affective disorder,¹⁷ RCT data are limited.^18,19 Bowden et al.²⁰ found no difference between lithium, valproate and placebo in the primary outcome measure, time to any mood episode, although valproate was superior to lithium and placebo on some secondary outcome measures. This study can be criticised for including patients who were 'not ill enough' and for not lasting 'long enough' (1 year). In another RCT,¹⁸ which lasted for 47 weeks, there was no difference in relapse rates between valproate and olanzapine. The study had no placebo arm and the attrition rate was high, so is difficult to interpret. A post-hoc analysis of data from this study found that patients with rapid cycling illness had a better very early response to valproate than to olanzapine but that this advantage was not maintained.¹⁹ Outcomes with respect to manic symptoms for those who did not have a rapid cycling illness were better at 1 year with olanzapine than valproate. In a further 20 month RCT of lithium versus valproate in patients with rapid cycling illness, both the relapse and attrition rate were high, and no difference in efficacy between valproate and lithium was apparent.²¹ More recently, the BALANCE study found lithium to be numerically superior to valproate, and the combination of lithium and valproate statistically superior to valproate alone.²² Aripiprazole in combination with valproate is superior to valproate alone.²³

NICE recommends valproate as a first-line option for the treatment of acute episodes of mania, in combination with an antidepressant for the treatment of acute episodes of depression, and for prophylaxis,²⁴ but importantly NOT in women of child-bearing potential.^24,25 Cochrane conclude that the evidence supporting the use of valproate as prophylaxis is limited,²⁶ yet use for this indication has substantially increased in recent years.²⁷

Valproate is sometimes used to treat aggressive behaviours of variable aetiology.²⁸ One small RCT (n = 16) failed to detect any advantage for risperidone augmented with valproate over risperidone alone in reducing hostility in patients with schizophrenia.²⁹ A mirror-image study found that, in patients with schizophrenia or bipolar disorder in a secure setting, valproate decreased agitation.³⁰

There is a small positive placebo controlled RCT of valproate in generalised anxiety disorder.³¹

Plasma levels

The pharmacokinetics of valproate are complex, following a three-compartmental model and showing protein-binding saturation. Plasma level monitoring is supposedly of more limited use than with lithium or carbamazepine.³² There may be a linear association between valproate serum levels and response in acute mania, with serum levels < 55 mg/L being no more effective than placebo and levels > 94 mg/L being associated with the most robust response,³³ although these data are weak.³² Note that this is the top of the reference range (for epilepsy) that is quoted on laboratory forms. Optimal serum levels during the maintenance phase are unknown, but are likely to be at least 50 mg/L.³⁴ Achieving therapeutic plasma levels rapidly using a loading dose regimen is generally well tolerated. Plasma levels can also be used to detect non-compliance or toxicity.

Adverse effects

Valproate can cause both gastric irritation and hyperammonaemia,³⁵ both of which can lead to nausea. Lethargy and confusion can occasionally occur with starting doses above 750 mg/day. Weight gain can be significant,³⁶ particularly when valproate is used in combination with clozapine. Valproate causes dose related tremor in up to one-quarter of patients.³⁷ In the majority of these patients it is intention/postural tremor that is problematic, but a very small proportion develop parkinsonism associated with cognitive decline; these symptoms are reversible when valproate is discontinued.³⁸

Hair loss with curly regrowth and peripheral oedema can occur, as can thrombocytopenia, leucopenia, red cell hypoplasia and pancreatitis.³⁹ Valproate can cause hyperandrogenism in women⁴⁰ and has been linked with the development of polycystic ovaries; the evidence supporting this association is conflicting. Valproate is a major human teratogen (see section on 'Pregnancy' in Chapter 7). Valproate may very rarely cause fulminant hepatic failure. Young children receiving multiple anticonvulsants are most at risk. Any patient with raised liver function tests (LFTs) (common in early treatment⁴¹) should be evaluated clinically and other markers of hepatic function, such as albumin and clotting time, should be checked.

Many side-effects of valproate are dose-related (peak plasma-level related) and increase in frequency and severity when the plasma level is > 100 mg/L. The once daily chrono form of sodium valproate does not produce as high peak plasma levels as the conventional formulation, and so may be better tolerated.

Valproate and other anticonvulsant drugs have been associated with an increased risk of suicidal behaviour,⁴² but this finding is not consistent across studies.⁴³ Patients with depression⁴⁴ or who take another anticonvulsant drug that increases the risk of developing depression may be a sub-group at greater risk.⁴⁵

Note that valproate is eliminated mainly through the kidneys, partly in the form of ketone bodies, and may give a false positive urine test for ketones.

Pre-treatment tests

Baseline full blood count (FBC), LFTs, and weight or BMI, are recommended by NICE.

On-treatment monitoring

NICE recommend that a FBC and LFTs should be repeated after 6 months, and that BMI should be monitored. Valproate summary of product characteristics (SPCs) recommend more frequent LFTs during the first 6 months, with albumin and clotting measured if enzyme levels are abnormal.

Discontinuation

It is unknown if abrupt discontinuation of valproate worsens the natural course of bipolar illness in the same way that discontinuation of lithium does. One small naturalistic retrospective study suggests that it might.⁴⁶ Until further data are available, if valproate is to be discontinued, it should be done slowly over at least a month.

Use in women of child-bearing age

Valproate is an established human teratogen. NICE recommend that alternative anticonvulsants are preferred in women with epilepsy⁴⁷ and that valproate should not be used to treat bipolar illness in women of child-bearing age.²⁴

The SPCs for sodium valproate and semi-sodium valproate^48,49 state that:

• these drugs should not be initiated in women of child-bearing potential without specialist advice (from a neurologist or psychiatrist)
• women who are trying to conceive and require valproate, should be prescribed prophylactic folate.

Women who have mania are likely to be sexually disinhibited. The risk of unplanned pregnancy is likely to be above population norms (where 50% of pregnancies are unplanned). If valproate cannot be avoided, adequate contraception should be ensured and prophylactic folate prescribed.

The teratogenic potential of valproate is not widely appreciated and many women of child-bearing age are not advised of the need for contraception or prophylactic folate.^50,51 Valproate may also cause impaired cognitive function in children exposed to valproate in utero.⁵² See section on 'Pregnancy' in Chapter 7.

Interactions with other drugs

Valproate is highly protein bound and can be displaced by other protein-bound drugs, such as aspirin, leading to toxicity. Aspirin also inhibits the metabolism of valproate; a dose of at least 300 mg aspirin is required.⁵³ Other, less strongly protein-bound drugs, such as warfarin, can be displaced by valproate, leading to higher free levels and toxicity. Valproate is hepatically metabolised; drugs that inhibit CYP enzymes can increase valproate levels (e.g. erythromycin, fluoxetine and cimetidine). Valproate can increase the plasma levels of some drugs, possibly by inhibition/competitive inhibition of their metabolism. Examples include tricyclic antidepressants (TCAs) (particularly clomipramine⁵⁴), lamotrigine,⁵⁵ quetiapine,⁵⁶ warfarin⁵⁷ and phenobarbital. Valproate may also significantly lower plasma olanzapine concentrations; the mechanism is unknown.⁵⁸

Pharmacodynamic interactions also occur. The anticonvulsant effect of valproate is antagonised by drugs that lower the seizure threshold (e.g. antipsychotics). Weight gain can be exacerbated by other drugs such as clozapine and olanzapine.

The prescribing and monitoring of valproate are summarised in Table 3.3.

Table 3.3 Valproate: prescribing and monitoring

References

1. Rosenberg G. The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees? Cell Mol Life Sci 2007; 64:2090–2103.
2. Kuendgen A et al. Valproic acid for the treatment of myeloid malignancies. Cancer 2007; 110:943–954.
3. Atmaca A et al. Valproic acid (VPA) in patients with refractory advanced cancer: a dose escalating phase I clinical trial. Br J Cancer 2007; 97:177–182.
4. Hallas J et al. Cancer risk in long-term users of valproate: a population-based case-control study. Cancer Epidemiol Biomarkers Prev 2009; 18:1714–1719.
5. Fisher C et al. Sodium valproate or valproate semisodium: is there a difference in the treatment of bipolar disorder? Psychiatr Bull 2003; 27:446–448.
6. Iqbal SU et al. Divalproex sodium vs. valproic acid: drug utilization patterns, persistence rates and predictors of hospitalization among VA patients diagnosed with bipolar disorder. J Clin Pharm Ther 2007; 32:625–632.
7. Wassef AA et al. Lower effectiveness of divalproex versus valproic acid in a prospective, quasi-experimental clinical trial involving 9,260 psychiatric admissions. Am J Psychiatry 2005; 162:330–339.
8. Bowden CL et al. Efficacy of divalproex vs lithium and placebo in the treatment of mania. The Depakote Mania Study Group. JAMA 1994; 271:918–924.
9. Freeman TW et al. A double-blind comparison of valproate and lithium in the treatment of acute mania. Am J Psychiatry 1992; 149:108–111.
10. Nasrallah HA et al. Carbamazepine and valproate for the treatment of bipolar disorder: a review of the literature. J Affect Disord 2006; 95:69–78.
11. Hirschfeld RM et al. A randomized, placebo-controlled, multicenter study of divalproex sodium extended-release in the acute treatment of mania. J Clin Psychiatry 2010; 71:426–432.
12. Bowden C et al. A 12-week, open, randomized trial comparing sodium valproate to lithium in patients with bipolar I disorder suffering from a manic episode. Int Clin Psychopharmacol 2008; 23:254–262.
13. Pope HG, Jr. et al. Valproate in the treatment of acute mania. A placebo-controlled study. Arch Gen Psychiatry 1991; 48:62–68.
14. Novick D et al. Translation of randomised controlled trial findings into clinical practice: comparison of olanzapine and valproate in the EMBLEM study. Pharmacopsychiatry 2009; 42:145–152.
15. Cipriani A et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet 2011; 378:1306–1315.
16. Smith LA et al. Valproate for the treatment of acute bipolar depression: systematic review and meta-analysis. J Affect Disord 2010; 122:1–9.
17. Calabrese JR et al. Spectrum of efficacy of valproate in 55 patients with rapid-cycling bipolar disorder. Am J Psychiatry 1990; 147:431–434.
18. Tohen M et al. Olanzapine versus divalproex sodium for the treatment of acute mania and maintenance of remission: a 47-week study. Am J Psychiatry 2003; 160:1263–1271.
19. Suppes T et al. Rapid versus non-rapid cycling as a predictor of response to olanzapine and divalproex sodium for bipolar mania and maintenance of remission: post hoc analyses of 47-week data. J Affect Disord 2005; 89:69–77.
20. Bowden CL et al. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group. Arch Gen Psychiatry 2000; 57:481–489.
21. Calabrese JR et al. A 20-month, double-blind, maintenance trial of lithium versus divalproex in rapid-cycling bipolar disorder. Am J Psychiatry 2005; 162:2152–2161.
22. Geddes JR et al. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet 2010; 375:385–395.
23. Marcus R et al. Efficacy of aripiprazole adjunctive to lithium or valproate in the long-term treatment of patients with bipolar I disorder with an inadequate response to lithium or valproate monotherapy: a multicenter, double-blind, randomized study. Bipolar Disord 2011; 13: 133–144.
24. National Institute for Health and Care Excellence. Bipolar disorder: the assessment and management of bipolar disorder in adults, children and young people in primary and secondary care. Draft for consultation, April 2014. http://www.nice.org.uk/
25. National Institute for Health and Care Excellence. Antenatal and postnatal mental health (update): full version. Clinical management and service 5 guidance. Draft for consultation. 2014. http://www.nice.org.uk/
26. Cipriani A et al. Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder. Cochrane Database Syst Rev 2013; 10: CD003196.
27. Hayes J et al. Prescribing trends in bipolar disorder: cohort study in the United Kingdom THIN primary care database 1995–2009. PLoS One 2011; 6:e28725.
28. Lindenmayer JP et al. Use of sodium valproate in violent and aggressive behaviors: a critical review. J Clin Psychiatry 2000; 61:123–128.
29. Citrome L et al. Risperidone alone versus risperidone plus valproate in the treatment of patients with schizophrenia and hostility. Int Clin Psychopharmacol 2007; 22:356–362.
30. Gobbi G et al. Efficacy of topiramate, valproate, and their combination on aggression/agitation behavior in patients with psychosis. J Clin Psychopharmacol 2006; 26:467–473.
31. Aliyev NA et al. Valproate (depakine-chrono) in the acute treatment of outpatients with generalized anxiety disorder without psychiatric comorbidity: randomized, double-blind placebo-controlled study. Eur Psychiatry 2008; 23:109–114.
32. Haymond J et al. Does valproic acid warrant therapeutic drug monitoring in bipolar affective disorder? Ther Drug Monit 2010; 32:19–29.
33. Allen MH et al. Linear relationship of valproate serum concentration to response and optimal serum levels for acute mania. Am J Psychiatry 2006; 163:272–275.
34. Taylor D et al. Doses of carbamazepine and valproate in bipolar affective disorder. Psychiatr Bull 1997; 21:221–223.
35. Segura-Bruna N et al. Valproate-induced hyperammonemic encephalopathy. Acta Neurol Scand 2006; 114:1–7.
36. El-Khatib F et al. Valproate, weight gain and carbohydrate craving: a gender study. Seizure 2007; 16:226–232.
37. Zadikoff C et al. Movement disorders in patients taking anticonvulsants. J Neurol Neurosurg Psychiatry 2007; 78:147–151.
38. Ristic AJ et al. The frequency of reversible parkinsonism and cognitive decline associated with valproate treatment: a study of 364 patients with different types of epilepsy. Epilepsia 2006; 47:2183–2185.
39. Gerstner T et al. Valproic acid-induced pancreatitis: 16 new cases and a review of the literature. J Gastroenterol 2007; 42:39–48.
40. Joffe H et al. Valproate is associated with new-onset oligoamenorrhea with hyperandrogenism in women with bipolar disorder. Biol Psychiatry 2006; 59:1078–1086.
41. Bjornsson E. Hepatotoxicity associated with antiepileptic drugs. Acta Neurol Scand 2008; 118:281–290.
42. Patorno E et al. Anticonvulsant medications and the risk of suicide, attempted suicide, or violent death. JAMA 2010; 303:1401–1409.
43. Gibbons RD et al. Relationship between antiepileptic drugs and suicide attempts in patients with bipolar disorder. Arch Gen Psychiatry 2009; 66:1354–1360.
44. Arana A et al. Suicide-related events in patients treated with antiepileptic drugs. N Engl J Med 2010; 363:542–551.
45. Andersohn F et al. Use of antiepileptic drugs in epilepsy and the risk of self-harm or suicidal behavior. Neurology 2010; 75:335–340.
46. Franks MA et al. Bouncing back: is the bipolar rebound phenomenon peculiar to lithium? A retrospective naturalistic study. J Psychopharmacol 2008; 22:452–456.
47. National Institute for Health and Clinical Excellence. The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. Clinical Guideline 137, 2012. http://guidance.nice.org.uk/CG137
48. Sanofi. Summary of Product Characteristics. Epilim Chrono 500 mg. 2013. http://www.medicines.org.uk/
49. Sanofi. Summary of Product Characteristics. Depakote 250 mg Tablets. 2013. http://www.medicines.org.uk/
50. James L et al. Informing patients of the teratogenic potential of mood stabilising drugs; a case notes review of the practice of psychiatrists. J Psychopharmacol 2007; 21:815–819.
51. James L et al. Mood stabilizers and teratogenicity—prescribing practice and awareness amongst practising psychiatrists. J Ment Health 2009; 18:137–143.
52. Meador KJ et al. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med 2009; 360:1597–1605.
53. Sandson NB et al. An interaction between aspirin and valproate: the relevance of plasma protein displacement drug-drug interactions. Am J Psychiatry 2006; 163:1891–1896.
54. Fehr C et al. Increase in serum clomipramine concentrations caused by valproate. J Clin Psychopharmacol 2000; 20:493–494.
55. Morris RG et al. Clinical study of lamotrigine and valproic acid in patients with epilepsy: using a drug interaction to advantage? Ther Drug Monit 2000; 22:656–660.
56. Aichhorn W et al. Influence of age, gender, body weight and valproate comedication on quetiapine plasma concentrations. Int Clin Psychopharmacol 2006; 21:81–85.
57. Gunes A et al. Inhibitory effect of valproic acid on cytochrome P450 2C9 activity in epilepsy patients. Basic Clin Pharmacol Toxicol 2007; 100:383–386.
58. Bergemann N et al. Valproate lowers plasma concentration of olanzapine. J Clin Psychopharmacol 2006; 26:432–434.

Carbamazepine

Mechanism of action¹

Carbamazepine blocks voltage-dependent sodium channels thus inhibiting repetitive neuronal firing. It reduces glutamate release and decreases the turnover of dopamine and nor-adrenaline. Carbamazepine has a similar molecular structure to TCAs.

As well as blocking voltage-dependent sodium channels, oxcarbazepine also increases potassium conductance and modulates high-voltage activated calcium channels.

Formulations

Carbamazepine is available as a liquid, chewable, immediate-release and controlled-release tablets. Conventional formulations generally have to be administered twoto three-times daily. The controlled release preparation can be given once or twice daily, and the reduced fluctuation in serum levels usually leads to improved tolerability. This preparation has a lower bioavailability and an increase in dose of 10–15% may be required.

Indications

Carbamazepine is primarily used as an anticonvulsant in the treatment of grand mal and focal seizures. It is also used in the treatment of trigeminal neuralgia and, in the UK, is licensed for the treatment of bipolar illness in patients who do not respond to lithium.

With respect to the treatment of mania, two placebo-controlled randomised studies have found the extended-release formulation of carbamazepine to be effective; in both studies, the response rate in the carbamazepine arm was twice that in the placebo arm.^2,3 Carbamazepine was not particularly well tolerated; the incidence of dizziness, somnolence and nausea was high. Another study found carbamazepine alone to be as effective as carbamazepine plus olanzapine.⁴ NICE does not recommend carbamazepine as a first-line treatment for mania.⁵

Open studies suggest that carbamazepine monotherapy has some efficacy in bipolar depression;⁶ note that the evidence base supporting other strategies is stronger (see section on 'Bipolar depression' in this chapter). Carbamazepine may also be useful in unipolar depression either alone⁷ or as an augmentation strategy.⁸

Carbamazepine is generally considered to be less effective than lithium in the prophylaxis of bipolar illness;⁹ several published studies report a low response rate and high drop-out rate. A meta-analysis (n = 464) failed to find a significant difference in efficacy between lithium and carbamazepine, but those who received carbamazepine were more likely to drop out of treatment because of side-effects.¹⁰ Lithium is considered to be superior to carbamazepine in reducing suicidal behaviour,¹¹ although data are not consistent.¹² NICE considers carbamazepine to be a third-line prophylactic agent.⁵ Three small studies suggest the related oxcarbazepine may have some prophylactic efficacy when used in combination with other mood stabilising drugs.^13–15

There are data supporting the use of carbamazepine in the management of alcohol withdrawal symptoms,¹⁶ although the high doses required initially are often poorly tolerated. Cochrane does not consider the evidence strong enough to support the use of carbamazepine for this indication.¹⁷ Carbamazepine has also been used to manage aggressive behaviour in patients with schizophrenia;¹⁸ the quality of data is weak and the mode of action unknown. There are a number of case reports and open case series that report on the use of carbamazepine in various psychiatric illnesses such as panic disorder, borderline personality disorder and episodic dyscontrol syndrome.

Plasma levels

When carbamazepine is used as an anticonvulsant, the therapeutic range is generally considered to be 4–12 mg/L, although the supporting evidence is not strong. In patients with affective illness, a dose of at least 600 mg/day and a plasma level of at least 7 mg/L may be required,¹⁹ although this is not a consistent finding.^4,7,20 Levels above 12 mg/L are associated with a higher side-effect burden.

Carbamazepine serum levels vary markedly within a dosage interval. It is therefore important to sample at a point in time where levels are likely to be reproducible for any given individual. The most appropriate way of monitoring is to take a trough level before the first dose of the day.

Carbamazepine is a hepatic enzyme inducer that induces its own metabolism as well as that of other drugs. An initial plasma half-life of around 30 hours is reduced to around 12 hours on chronic dosing. For this reason, plasma levels should be checked 2–4 weeks after an increase in dose to ensure that the desired level is still being obtained.

Most published clinical trials that demonstrate the efficacy of carbamazepine as a mood stabiliser use doses that are significantly higher (800–1200 mg/day) than those commonly prescribed in UK clinical practice.²¹

Adverse effects¹

The main side-effects associated with carbamazepine therapy are dizziness, diplopia, drowsiness, ataxia, nausea and headaches. They can sometimes be avoided by starting with a low dose and increasing slowly. Avoiding high peak blood levels by splitting the dose throughout the day, or using a controlled release formulation, may also help. Dry mouth, oedema and hyponatraemia are also common. Sexual dysfunction can occur, probably mediated through reduced testosterone levels.²² Around 3% of patients treated with carbamazepine develop a generalised erythematous rash. Serious exfoliative dermatological reactions can rarely occur; vulnerability is genetically determined,²³ and genetic testing of people of Han Chinese or Thai origin is recommended before carbamazepine is prescribed. Carbamazepine is a known human teratogen (see section on 'Pregnancy' in Chapter 7).

Carbamazepine commonly causes a chronic low white blood cell (WBC) count. One patient in 20,000 develops agranulocytosis and/or aplastic anaemia.²⁴ Raised alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) are common (a GGT of 2–3 times normal is rarely a cause for concern²⁵). A delayed multi-organ hypersensitivity reaction rarely occurs, mainly manifesting itself as various skin reactions, a low WBC count, and abnormal LFTs. Fatalities have been reported.^25,26 There is no clear timescale for these events.

Some anticonvulsant drugs have been associated with an increased risk of suicidal behaviour. Carbamazepine has not been implicated, either in general,^27,28 or more specifically, in those with bipolar illness.²⁹

Pre-treatment tests

Baseline U&Es, FBC and LFTs are recommended by NICE. A baseline measure of weight is also desirable.

On-treatment monitoring

NICE recommend that U&Es, FBC and LFTs should be repeated after 6 months, and that weight (or BMI) should also be monitored.

Discontinuation

It is not known if abrupt discontinuation of carbamazepine worsens the natural course of bipolar illness in the same way that abrupt cessation of lithium does. In one small case series (n = 6), one patient developed depression within 1 month of discontinuation,³⁰ while in another small case series (n = 4), three patients had a recurrence of their mood disorder within 3 months.³¹ Until further data are available, if carbamazepine is to be discontinued, it should be done slowly (over at least a month).

Use in women of child-bearing age

Carbamazepine is an established human teratogen (see section on 'Pregnancy' in Chapter 7).

Women who have mania are likely to be sexually disinhibited. The risk of unplanned pregnancy is likely to be above population norms (where 50% of pregnancies are unplanned). If carbamazepine cannot be avoided, adequate contraception should be ensured (note the interaction between carbamazepine and oral contraceptives outlined below) and prophylactic folate prescribed.

Interactions with other drugs^32–35

Carbamazepine is a potent inducer of hepatic cytochrome enzymes and is metabolised by CYP3A4. Plasma levels of most antidepressants, most antipsychotics, benzodiazepines, some cholinesterase inhibitors, methadone, thyroxine, theophylline, oestrogens and other steroids may be reduced by carbamazepine, resulting in treatment failure. Patients requiring contraception should either receive a preparation containing not less than 50 μg oestrogen or use a non-hormonal method. Drugs that inhibit CYP3A4 will increase carbamazepine plasma levels and may precipitate toxicity. Examples include cimetidine, diltiazem, verapamil, erythromycin and some selective serotonin reuptake inhibitors (SSRIs).

Pharmacodynamic interactions also occur. The anticonvulsant activity of carbamazepine is reduced by drugs that lower the seizure threshold (e.g. antipsychotics and antidepressants), the potential for carbamazepine to cause neutropenia may be increased by other drugs that have the potential to depress the bone marrow (e.g. clozapine), and the risk of hyponatraemia may be increased by other drugs that have the potential to deplete sodium (e.g. diuretics). Neurotoxicity has been reported when carbamazepine is used in combination with lithium. This is rare.

Table 3.4 Carbamazepine: prescribing and monitoring

As carbamazepine is structurally similar to TCAs, in theory it should not be given within 14 days of discontinuing a monoamine oxidase inhibitor (MAOI).

The prescribing and monitoring of carbamazepine is summarised in Table 3.4.

References

1. Novartis Pharmaceuticals UK Ltd. Summary of Product Characteristics. Tegretol Prolonged Release 200 mg and 400 mg Tablets (formerly Tegretol retard). 2014. http://www.medicines.org.uk/
2. Weisler RH et al. A multicenter, randomized, double-blind, placebo-controlled trial of extended-release carbamazepine capsules as monotherapy for bipolar disorder patients with manic or mixed episodes. J Clin Psychiatry 2004; 65:478–484.
3. Weisler RH et al. Extended-release carbamazepine capsules as monotherapy for acute mania in bipolar disorder: a multicenter, randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2005; 66:323–330.
4. Tohen M et al. Olanzapine plus carbamazepine v. carbamazepine alone in treating manic episodes. Br J Psychiatry 2008; 192:135–143.
5. National Institute for Health and Care Excellence. Bipolar disorder: the assessment and management of bipolar disorder in adults, children and young people in primary and secondary care. Draft for consultation, April 2014. https://www.nice.org.uk/
6. Dilsaver SC et al. Treatment of bipolar depression with carbamazepine: results of an open study. Biol Psychiatry 1996; 40:935–937.
7. Zhang ZJ et al. The effectiveness of carbamazepine in unipolar depression: a double-blind, randomized, placebo-controlled study. J Affect Disord 2008; 109:91–97.
8. Kramlinger KG et al. The addition of lithium to carbamazepine. Antidepressant efficacy in treatment-resistant depression. Arch Gen Psychiatry 1989; 46:794–800.
9. Nasrallah HA et al. Carbamazepine and valproate for the treatment of bipolar disorder: a review of the literature. J Affect Disord 2006; 95:69–78.
10. Ceron-Litvoc D et al. Comparison of carbamazepine and lithium in treatment of bipolar disorder: a systematic review of randomized controlled trials. Hum Psychopharmacol 2009; 24:19–28.
11. Kleindienst N et al. Differential efficacy of lithium and carbamazepine in the prophylaxis of bipolar disorder: results of the MAP study. Neuropsychobiology 2000; 42 Suppl 1:2–10.
12. Yerevanian BI et al. Bipolar pharmacotherapy and suicidal behavior. Part I: Lithium, divalproex and carbamazepine. J Affect Disord 2007; 103:5–11.
13. Vieta E et al. A double-blind, randomized, placebo-controlled prophylaxis trial of oxcarbazepine as adjunctive treatment to lithium in the long-term treatment of bipolar I and II disorder. Int J Neuropsychopharmacol 2008; 11:445–452.
14. Conway CR et al. An open-label trial of adjunctive oxcarbazepine for bipolar disorder. J Clin Psychopharmacol 2006; 26:95–97.
15. Juruena MF et al. Bipolar I and II disorder residual symptoms: oxcarbazepine and carbamazepine as add-on treatment to lithium in a double-blind, randomized trial. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33:94–99.
16. Malcolm R et al. The effects of carbamazepine and lorazepam on single versus multiple previous alcohol withdrawals in an outpatient randomized trial. J Gen Intern Med 2002; 17:349–355.
17. Minozzi S et al. Anticonvulsants for alcohol withdrawal. Cochrane Database Syst Rev 2010;CD005064.
18. Brieden T et al. Psychopharmacological treatment of aggression in schizophrenic patients. Pharmacopsychiatry 2002; 35:83–89.
19. Taylor D et al. Doses of carbamazepine and valproate in bipolar affective disorder. Psychiatr Bull 1997; 21:221–223.
20. Simhandl C et al. The comparative efficacy of carbamazepine low and high serum level and lithium carbonate in the prophylaxis of affective disorders. J Affect Disord 1993; 28:221–231.
21. Taylor DM et al. Prescribing and monitoring of carbamazepine and valproate—a case note review. Psychiatr Bull 2000; 24:174–177.
22. Lossius MI et al. Reversible effects of antiepileptic drugs on reproductive endocrine function in men and women with epilepsy–a prospective randomized double-blind withdrawal study. Epilepsia 2007; 48:1875–1882.
23. Hung SI et al. Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet Genomics 2006; 16:297–306.
24. Kaufman DW et al. Drugs in the aetiology of agranulocytosis and aplastic anaemia. Eur J Haematol Suppl 1996; 60:23–30.
25. Bjornsson E. Hepatotoxicity associated with antiepileptic drugs. Acta Neurol Scand 2008; 118:281–290.
26. Ganeva M et al. Carbamazepine-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: report of four cases and brief review. Int J Dermatol 2008; 47:853–860.
27. Patorno E et al. Anticonvulsant medications and the risk of suicide, attempted suicide, or violent death. JAMA 2010; 303:1401–1409.
28. Andersohn F et al. Use of antiepileptic drugs in epilepsy and the risk of self-harm or suicidal behavior. Neurology 2010; 75:335–340.
29. Gibbons RD et al. Relationship between antiepileptic drugs and suicide attempts in patients with bipolar disorder. Arch Gen Psychiatry 2009; 66:1354–1360.
30. Macritchie KA et al. Does 'rebound mania' occur after stopping carbamazepine? A pilot study. J Psychopharmacol 2000; 14:266–268.
31. Franks MA et al. Bouncing back: is the bipolar rebound phenomenon peculiar to lithium? A retrospective naturalistic study. J Psychopharmacol 2008; 22:452–456.
32. Spina E et al. Clinical significance of pharmacokinetic interactions between antiepileptic and psychotropic drugs. Epilepsia 2002; 43 Suppl 2: 37–44.
33. Patsalos PN et al. The importance of drug interactions in epilepsy therapy. Epilepsia 2002; 43:365–385.
34. Crawford P. Interactions between antiepileptic drugs and hormonal contraception. CNS Drugs 2002; 16:263–272.
35. Citrome L et al. Pharmacokinetics of aripiprazole and concomitant carbamazepine. J Clin Psychopharmacol 2007; 27:279–283.

Antipsychotics in bipolar disorder

It is unhelpful to think of antipsychotic drugs as having only 'antipsychotic' actions. Individual antipsychotics variously possess sedative, anxiolytic, antimanic, mood-stabilising and antidepressant properties. Some antipsychotics (quetiapine and olanzapine) show all of these activities.

First-generation antipsychotics (FGAs) have long been used in mania and several studies support their use in a variety of hypomanic and manic presentations.^1–3 Their effectiveness seems to be enhanced by the addition of a mood stabiliser.^4,5 In the longer-term treatment of bipolar affective disorder, FGAs are widely used (presumably as prophylaxis)⁶ but robust supporting data are absent.⁷ The observation that typical antipsychotics are associated with both depression and tardive dyskinesia in bipolar patients militates against their long-term use.^7–9 Certainly the use of second-generation antipsychotics (SGAs) seems less likely to cause depression than treatment with haloperidol.¹⁰ The use of FGA depots is common in practice but poorly supported and seems to be associated with a high risk of depression.¹¹

Among newer antipsychotics, olanzapine, risperidone, quetiapine, aripiprazole and asenapine have been most robustly evaluated and are licensed in many countries for the treatment of mania. Olanzapine is more effective than placebo in mania,^12,13 and at least as effective as valproate semi-sodium^14,15 and lithium.^16,17 As with FGAs, olanzapine may be most effective when used in combination with a mood-stabiliser^18,19 (although in one study, olanzapine + carbamazepine was no better than carbamazepine alone²⁰). Data suggest olanzapine may offer benefits in longer-term treatment;^21,22 it may be more effective than lithium,²³ and it is formally licensed as prophylaxis.

Data relating to quetiapine^24–26 suggest robust efficacy in all aspects of bipolar affective disorder including prevention of bipolar depression.²⁷ Aripiprazole is effective in mania both alone^28–30 and as an add-on agent,³¹ and in long-term prophylaxis.^32,33 Clozapine seems to be effective in refractory bipolar conditions, including refractory mania.^34–37 Risperidone has shown efficacy in mania,³⁸ particularly in combination with a mood-stabiliser.^2,39 Risperidone long acting injection is also effective⁴⁰ (note though that the pharmacokinetics of this formulation generally render it an unsuitable choice for the acute treatment of mania). There are few data for amisulpride⁴¹ rather more for ziprasidone⁴² and effectively none for lurasidone (notwithstanding its effect as an acute treatment for bipolar depression^43,44) or iloperidone.

Asenapine is given by the sublingual route and is effective in mania.^45,46 Efficacy seems to be maintained in the longer term.⁴⁷ Asenapine is less sedative than olanzapine with a similar (low) propensity for akathisia and other movement disorders^46,47 and is less likely than olanzapine to cause weight gain and metabolic disturbance.⁴⁸

Overall, antipsychotics (particularly haloperidol, olanzapine and risperidone) may be more effective than traditional mood stabilisers in the treatment of mania,⁴⁹ and quetiapine is similarly effective but better tolerated than aripiprazole or lithium.⁴⁹

References

1. Prien RF et al. Comparison of lithium carbonate and chlorpromazine in the treatment of mania. Report of the Veterans Administration and National Institute of Mental Health Collaborative Study Group. Arch Gen Psychiatry 1972; 26:146–153.
2. Sachs GS et al. Combination of a mood stabilizer with risperidone or haloperidol for treatment of acute mania: a double-blind, placebocontrolled comparison of efficacy and safety. Am J Psychiatry 2002; 159:1146–1154.
3. McElroy SL et al. A randomized comparison of divalproex oral loading versus haloperidol in the initial treatment of acute psychotic mania. J Clin Psychiatry 1996; 57:142–146.
4. Chou JC et al. Acute mania: haloperidol dose and augmentation with lithium or lorazepam. J Clin Psychopharmacol 1999; 19:500–505.
5. Small JG et al. A placebo-controlled study of lithium combined with neuroleptics in chronic schizophrenic patients. Am J Psychiatry 1975; 132:1315–1317.
6. Soares JC et al. Adjunctive antipsychotic use in bipolar patients: an open 6-month prospective study following an acute episode. J Affect Disord 1999; 56:1–8.
7. Keck PE, Jr. et al. Anticonvulsants and antipsychotics in the treatment of bipolar disorder. J Clin Psychiatry 1998; 59 Suppl 6:74–81.
8. Tohen M et al. Antipsychotic agents and bipolar disorder. J Clin Psychiatry 1998; 59 Suppl 1:38–48.
9. Zarate CA, Jr. et al. Double-blind comparison of the continued use of antipsychotic treatment versus its discontinuation in remitted manic patients. Am J Psychiatry 2004; 161:169–171.
10. Goikolea JM et al. Lower rate of depressive switch following antimanic treatment with second-generation antipsychotics versus haloperidol. J Affect Disord 2013; 144:191–198.
11. Gigante AD et al. Long-acting injectable antipsychotics for the maintenance treatment of bipolar disorder. CNS Drugs 2012; 26:403–420.
12. Tohen M et al. Olanzapine versus placebo in the treatment of acute mania. Olanzapine HGEH Study Group. Am J Psychiatry 1999; 156:702–709.
13. Tohen M et al. Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled study. The Olanzipine HGGW Study Group. Arch Gen Psychiatry 2000; 57:841–849.
14. Tohen M et al. Olanzapine versus divalproex in the treatment of acute mania. Am J Psychiatry 2002; 159:1011–1017.
15. Tohen M et al. Olanzapine versus divalproex versus placebo in the treatment of mild to moderate mania: a randomized, 12-week, double-blind study. J Clin Psychiatry 2008; 69:1776–1789.
16. Berk M et al. Olanzapine compared to lithium in mania: a double-blind randomized controlled trial. Int Clin Psychopharmacol 1999; 14:339–343.
17. Niufan G et al. Olanzapine versus lithium in the acute treatment of bipolar mania: a double-blind, randomized, controlled trial. J Affect Disord 2008; 105:101–108.
18. Tohen M et al. Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy. Arch Gen Psychiatry 2002; 59:62–69.
19. Tohen M et al. Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabiliser v. mood stabiliser alone. Br J Psychiatry 2004; 184:337–345.
20. Tohen M et al. Olanzapine plus carbamazepine v. carbamazepine alone in treating manic episodes. Br J Psychiatry 2008; 192:135–143.
21. Sanger TM et al. Long-term olanzapine therapy in the treatment of bipolar I disorder: an open-label continuation phase study. J Clin Psychiatry 2001; 62:273–281.
22. Vieta E et al. Olanzapine as long-term adjunctive therapy in treatment-resistant bipolar disorder. J Clin Psychopharmacol 2001; 21:469–473.
23. Tohen M et al. Olanzapine versus lithium in the maintenance treatment of bipolar disorder: a 12-month, randomized, double-blind, controlled clinical trial. Am J Psychiatry 2005; 162:1281–1290.
24. Ghaemi SN et al. The use of quetiapine for treatment-resistant bipolar disorder: a case series. Ann Clin Psychiatry 1999; 11:137–140.
25. Sachs G et al. Quetiapine with lithium or divalproex for the treatment of bipolar mania: a randomized, double-blind, placebo-controlled study. Bipolar Disord 2004; 6:213–223.
26. Altamura AC et al. Efficacy and tolerability of quetiapine in the treatment of bipolar disorder: preliminary evidence from a 12-month open label study. J Affect Disord 2003; 76:267–271.
27. Young AH et al. A randomised, placebo-controlled 52-week trial of continued quetiapine treatment in recently depressed patients with bipolar I and bipolar II disorder. World J Biol Psychiatry 2014; 15:96–112.
28. Sachs G et al. Aripiprazole in the treatment of acute manic or mixed episodes in patients with bipolar I disorder: a 3-week placebo-controlled study. J Psychopharmacol 2006; 20:536–546.
29. Keck PE et al. Aripiprazole monotherapy in the treatment of acute bipolar I mania: a randomized, double-blind, placeboand lithiumcontrolled study. J Affect Disord 2009; 112:36–49.
30. Young AH et al. Aripiprazole monotherapy in acute mania: 12-week randomised placeboand haloperidol-controlled study. The British Journal of Psychiatry 2009; 194:40–48.
31. Vieta E et al. Efficacy of adjunctive aripiprazole to either valproate or lithium in bipolar mania patients partially nonresponsive to valproate/ lithium monotherapy: a placebo-controlled study. Am J Psychiatry 2008; 165:1316–1325.
32. Keck PE, Jr. et al. Aripiprazole monotherapy for maintenance therapy in bipolar I disorder: a 100-week, double-blind study versus placebo. J Clin Psychiatry 2007; 68:1480–1491.
33. Vieta E et al. Assessment of safety, tolerability and effectiveness of adjunctive aripiprazole to lithium/valproate in bipolar mania: a 46-week, open-label extension following a 6-week double-blind study. Curr Med Res Opin 2010; 26:1485–1496.
34. Calabrese JR et al. Clozapine for treatment-refractory mania. Am J Psychiatry 1996; 153:759–764.
35. Green AI et al. Clozapine in the treatment of refractory psychotic mania. Am J Psychiatry 2000; 157:982–986.
36. Kimmel SE et al. Clozapine in treatment-refractory mood disorders. J Clin Psychiatry 1994; 55 Suppl B:91–93.
37. Chang JS et al. The effects of long-term clozapine add-on therapy on the rehospitalization rate and the mood polarity patterns in bipolar disorders. J Clin Psychiatry 2006; 67:461–467.
38. Segal J et al. Risperidone compared with both lithium and haloperidol in mania: a double-blind randomized controlled trial. Clin Neuropharmacol 1998; 21:176–180.
39. Vieta E et al. Risperidone in the treatment of mania: efficacy and safety results from a large, multicentre, open study in Spain. J Affect Disord 2002; 72:15–19.
40. Quiroz JA et al. Risperidone long-acting injectable monotherapy in the maintenance treatment of bipolar I disorder. Biol Psychiatry 2010; 68:156–162.
41. Vieta E et al. An open-label study of amisulpride in the treatment of mania. J Clin Psychiatry 2005; 66:575–578.
42. Vieta E et al. Ziprasidone in the treatment of acute mania: a 12-week, placebo-controlled, haloperidol-referenced study. J Psychopharmacol 2010; 24:547–558.
43. Loebel A et al. Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry 2014; 171:160–168.
44. Loebel A et al. Lurasidone as adjunctive therapy with lithium or valproate for the treatment of bipolar I depression: a randomized, doubleblind, placebo-controlled study. Am J Psychiatry 2014; 171:169–177.
45. McIntyre RS et al. Asenapine in the treatment of acute mania in bipolar I disorder: a randomized, double-blind, placebo-controlled trial. J Affect Disord 2010; 122:27–38.
46. McIntyre RS et al. Asenapine versus olanzapine in acute mania: a double-blind extension study. Bipolar Disord 2009; 11:815–826.
47. McIntyre RS et al. Asenapine for long-term treatment of bipolar disorder: a double-blind 40-week extension study. J Affect Disord 2010; 126:358–365.
48. Kemp DE et al. Weight change and metabolic effects of asenapine in patients with schizophrenia and bipolar disorder. J Clin Psychiatry 2014; 75:238–245.
49. Cipriani A et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet 2011; 378:1306–1315.

Treatment of acute mania or hypomania

Drug treatment is the mainstay of therapy for mania and hypomania. Both antipsychotics and so-called mood stabilisers are effective. Sedative and anxiolytic drugs (e.g. benzodiazepines) may add to the effects of these drugs. Drug choice is made difficult by the dearth of direct comparisons and so no drug can be recommended over another on efficacy grounds. However, a multiple treatments meta-analysis¹ (which allows indirect comparison) suggested that olanzapine, risperidone haloperidol and quetiapine had the best combination of efficacy and acceptability. The added benefit of antipsychotic–mood stabiliser combinations (compared with mood-stabiliser alone) is established for those relapsing while on mood stabilisers, but unclear for those presenting on no treatment.^2–6

Figure 3.1 Treatment of acute mania or hypomania.^2–15 Note that lithium may be relatively less effective in mixed states²¹ or substance misuse.²²

Figure 3.1 outlines a treatment strategy for mania and hypomania. These recommendations are based on UK NICE guidelines,³ the British Association of Psychopharmacology guidelines,⁴ American Psychiatric Association guidelines⁵ and individual references cited. Where an antipsychotic is recommended, choose from those licensed for mania/ bipolar disorder, i.e. most conventional drugs (see individual labels/SPCs), aripiprazole, asenapine, olanzapine, risperidone and quetiapine.

Those drugs with the best evidence for effective treatment of mania are shown in Table 3.5. Other possible treatments are shown in Table 3.6. The relative costs of drugs for the treatment of mania in the UK are shown in Table 3.7.

Table 3.5 Drug treatment of mania: suggested doses

Table 3.6 Other possible drug treatments for mania (listed in alphabetical order)

Table 3.7 Drugs for acute mania: relative costs

References

1. Cipriani A et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet 2011; 378:1306–1315.
2. Smith LA et al. Acute bipolar mania: a systematic review and meta-analysis of co-therapy vs. monotherapy. Acta Psychiatr Scand 2007; 115:12–20.
3. National Institute for Health and Care Excellence. Bipolar disorder: the assessment and management of bipolar disorder in adults, children and young people in primary and secondary care. Draft for consultation, April 2014. https://www.nice.org.uk/
4. Goodwin GM. Evidence-based guidelines for treating bipolar disorder: revised second edition–recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2009; 23:346–388.
5. American Psychiatric Association. Guideline Watch: Practice guideline for the treatment of patients with bipolar disorder, 2nd edn. Washington DC: American Psychiatric Association; 2005. DOI: 10.1176/appi.books.9780890423363.148430.
6. Sachs GS. Decision tree for the treatment of bipolar disorder. J Clin Psychiatry 2003; 64 Suppl 8:35–40.
7. Tohen M et al. A 12-week, double-blind comparison of olanzapine vs haloperidol in the treatment of acute mania. Arch Gen Psychiatry 2003; 60:1218–1226.
8. Baldessarini RJ et al. Olanzapine versus placebo in acute mania treatment responses in subgroups. J Clin Psychopharmacol 2003; 23:370–376.
9. Sachs G et al. Quetiapine with lithium or divalproex for the treatment of bipolar mania: a randomized, double-blind, placebo-controlled study. Bipolar Disord 2004; 6:213–223.
10. Yatham LN et al. Quetiapine versus placebo in combination with lithium or divalproex for the treatment of bipolar mania. J Clin Psychopharmacol 2004; 24:599–606.
11. Yatham LN et al. Risperidone plus lithium versus risperidone plus valproate in acute and continuation treatment of mania. Int Clin Psychopharmacol 2004; 19:103–109.
12. Bowden CL et al. Risperidone in combination with mood stabilizers: a 10-week continuation phase study in bipolar I disorder. J Clin Psychiatry 2004; 65:707–714.
13. Hirschfeld RM et al. Rapid antimanic effect of risperidone monotherapy: a 3-week multicenter, double-blind, placebo-controlled trial. Am J Psychiatry 2004; 161:1057–1065.
14. Bowden CL et al. A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder. J Clin Psychiatry 2005; 66:111–121.
15. Khanna S et al. Risperidone in the treatment of acute mania: double-blind, placebo-controlled study. Br J Psychiatry 2005; 187:229–234.
16. Sachs GS et al. Adjunctive clonazepam for maintenance treatment of bipolar affective disorder. J Clin Psychopharmacol 1990; 10:42–47.
17. Modell JG et al. Inpatient clinical trial of lorazepam for the management of manic agitation. J Clin Psychopharmacol 1985; 5:109–113.
18. Curtin F et al. Clonazepam and lorazepam in acute mania: a Bayesian meta-analysis. J Affect Disord 2004; 78:201–208.
19. Taylor D et al. Doses of carbamazepine and valproate in bipolar affective disorder. Psychiatr Bull 1997; 21:221–223.
20. Allen MH et al. Linear relationship of valproate serum concentration to response and optimal serum levels for acute mania. Am J Psychiatry 2006; 163:272–275.
21. Swann AC et al. Lithium treatment of mania: clinical characteristics, specificity of symptom change, and outcome. Psychiatry Res 1986; 18:127–141.
22. Goldberg JF et al. A history of substance abuse complicates remission from acute mania in bipolar disorder. J Clin Psychiatry 1999; 60:733–740.
23. Bowden CL et al. Efficacy of valproate versus lithium in mania or mixed mania: a randomized, open 12-week trial. Int Clin Psychopharmacol 2010; 25:60–67.
24. McElroy SL et al. Randomized, double-blind, placebo-controlled study of divalproex extended release loading monotherapy in ambulatory bipolar spectrum disorder patients with moderate-to-severe hypomania or mild mania. J Clin Psychiatry 2010; 71:557–565.
25. Hirschfeld RM et al. A randomized, placebo-controlled, multicenter study of divalproex sodium extended-release in the acute treatment of mania. J Clin Psychiatry 2010; 71:426–432.
26. McElroy SL et al. A randomized comparison of divalproex oral loading versus haloperidol in the initial treatment of acute psychotic mania. J Clin Psychiatry 1996; 57:142–146.
27. Hirschfeld RM et al. Safety and tolerability of oral loading divalproex sodium in acutely manic bipolar patients. J Clin Psychiatry 1999; 60:815–818.
28. Hirschfeld RM et al. The safety and early efficacy of oral-loaded divalproex versus standard-titration divalproex, lithium, olanzapine, and placebo in the treatment of acute mania associated with bipolar disorder. J Clin Psychiatry 2003; 64:841–846.
29. Jagadheesan K et al. Acute antimanic efficacy and safety of intravenous valproate loading therapy: an open-label study. Neuropsychobiology 2003; 47:90–93.
30. Sekhar S et al. Efficacy of sodium valproate and haloperidol in the management of acute mania: a randomized open-label comparative study. J Clin Pharmacol 2010; 50:688–692.
31. Young AH et al. Aripiprazole monotherapy in acute mania: 12-week randomised placeboand haloperidol-controlled study. Br J Psychiatry 2009; 194:40–48.
32. Keck PE et al. Aripiprazole monotherapy in the treatment of acute bipolar I mania: a randomized, double-blind, placeboand lithiumcontrolled study. J Affect Disord 2009; 112:36–49.
33. Pajonk FG et al. Rapid dose titration of quetiapine for the treatment of acute schizophrenia and acute mania: a case series. J Psychopharmacol 2006; 20:119–124.
34. Machado-Vieira R et al. A double-blind, randomized, placebo-controlled 4-week study on the efficacy and safety of the purinergic agents allopurinol and dipyridamole adjunctive to lithium in acute bipolar mania. J Clin Psychiatry 2008; 69:1237–1245.
35. Fan A et al. Allopurinol augmentation in the outpatient treatment of bipolar mania: a pilot study. Bipolar Disord 2012; 14:206–210.
36. Mahmood T et al. Clozapine in the management of bipolar and schizoaffective manic episodes resistant to standard treatment. Aust N Z J Psychiatry 1997; 31:424–426.
37. Green AI et al. Clozapine in the treatment of refractory psychotic mania. Am J Psychiatry 2000; 157:982–986.
38. Macdonald KJ et al. Newer antiepileptic drugs in bipolar disorder: rationale for use and role in therapy. CNS Drugs 2002; 16:549–562.
39. Cabras PL et al. Clinical experience with gabapentin in patients with bipolar or schizoaffective disorder: results of an open-label study. J Clin Psychiatry 1999; 60:245–248.
40. Pande AC et al. Gabapentin in bipolar disorder: a placebo-controlled trial of adjunctive therapy. Gabapentin Bipolar Disorder Study Group. Bipolar Disord 2000; 2 (3 Pt 2):249–255.
41. Vieta E et al. A double-blind, randomized, placebo-controlled, prophylaxis study of adjunctive gabapentin for bipolar disorder. J Clin Psychiatry 2006; 67:473–477.
42. Calabrese JR et al. Spectrum of activity of lamotrigine in treatment-refractory bipolar disorder. Am J Psychiatry 1999; 156:1019–1023.
43. Bowden CL et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry 2003; 60:392–400.
44. Grunze H et al. Levetiracetam in the treatment of acute mania: an open add-on study with an on-off-on design. J Clin Psychiatry 2003; 64:781–784.
45. Goldberg JF et al. Levetiracetam for acute mania (Letter). Am J Psychiatry 2002; 159:148.
46. Koukopoulos A et al. Antimanic and mood-stabilizing effect of memantine as an augmenting agent in treatment-resistant bipolar disorder. Bipolar Disord 2010; 12:348–349.
47. Benedetti A et al. Oxcarbazepine as add-on treatment in patients with bipolar manic, mixed or depressive episode. J Affect Disord 2004; 79:273–277.
48. Lande RG. Oxcarbazepine: Efficacy, safety, and tolerability in the treatment of mania. Int J Psychiatry Clin Pract 2004; 8:37–40.
49. Ghaemi SN et al. Oxcarbazepine treatment of bipolar disorder. J Clin Psychiatry 2003; 64:943–945.
50. Pratoomsri W et al. Oxcarbazepine in the treatment of bipolar disorder: a review. Can J Psychiatry 2006; 51:540–545.
51. Juruena MF et al. Bipolar I and II disorder residual symptoms: oxcarbazepine and carbamazepine as add-on treatment to lithium in a doubleblind, randomized trial. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33:94–99.
52. Suppes T et al. Comparison of two anticonvulsants in a randomized, single-blind treatment of hypomanic symptoms in patients with bipolar disorder. Aust N Z J Psychiatry 2007; 41:397–402.
53. Vieta E et al. A double-blind, randomized, placebo-controlled prophylaxis trial of oxcarbazepine as adjunctive treatment to lithium in the long-term treatment of bipolar I and II disorder. Int J Neuropsychopharmacol 2008; 11:445–452.
54. Wagner KD et al. A double-blind, randomized, placebo-controlled trial of oxcarbazepine in the treatment of bipolar disorder in children and adolescents. Am J Psychiatry 2006; 163:1179–1186.
55. Mishory A et al. Phenytoin as an antimanic anticonvulsant: a controlled study. Am J Psychiatry 2000; 157:463–465.
56. Akhondzadeh S et al. Ritanserin as an adjunct to lithium and haloperidol for the treatment of medication-naive patients with acute mania: a double blind and placebo controlled trial. BMC Psych 2003; 3:7.
57. Zarate CA, Jr. et al. Efficacy of a protein kinase C inhibitor (tamoxifen) in the treatment of acute mania: a pilot study. Bipolar Disord 2007; 9:561–570.
58. Yildiz A et al. Protein kinase C inhibition in the treatment of mania: a double-blind, placebo-controlled trial of tamoxifen. Arch Gen Psychiatry 2008; 65:255–263.
59. Amrollahi Z et al. Double-blind, randomized, placebo-controlled 6-week study on the efficacy and safety of the tamoxifen adjunctive to lithium in acute bipolar mania. J Affect Disord 2011; 129:327–331.
60. Grunze HC et al. Antimanic efficacy of topiramate in 11 patients in an open trial with an on-off-on design. J Clin Psychiatry 2001; 62:464–468.
61. Yatham LN et al. Third generation anticonvulsants in bipolar disorder: a review of efficacy and summary of clinical recommendations. J Clin Psychiatry 2002; 63:275–283.
62. Vieta E et al. 1-year follow-up of patients treated with risperidone and topiramate for a manic episode. J Clin Psychiatry 2003; 64:834–839.
63. Vieta E et al. Use of topiramate in treatment-resistant bipolar spectrum disorders. J Clin Psychopharmacol 2002; 22:431–435.
64. Applebaum J et al. Rapid tryptophan depletion as a treatment for acute mania: a double-blind, pilot-controlled study. Bipolar Disord 2007; 9:884–887.
65. Keck PE, Jr. et al. Ziprasidone in the treatment of acute bipolar mania: a three-week, placebo-controlled, double-blind, randomized trial. Am J Psychiatry 2003; 160:741–748.
66. Potkin SG et al. Ziprasidone in acute bipolar mania: a 21-day randomized, double-blind, placebo-controlled replication trial. J Clin Psychopharmacol 2005; 25:301–310.
67. Vieta E et al. Ziprasidone in the treatment of acute mania: a 12-week, placebo-controlled, haloperidol-referenced study. J Psychopharmacol 2010; 24:547–558.

Bipolar depression

Bipolar depression is a common and debilitating disorder which differs from unipolar disorder in severity, time course, recurrence and response to drug treatment. Episodes of bipolar depression are, compared with unipolar depression, more rapid in onset, more frequent, more severe, shorter and more likely to involve delusions and reverse neurovegetative symptoms such as hyperphagia and hypersomnia.^1–3 Around 15% of people with bipolar affective disorder commit suicide,⁴ a statistic which aptly reflects the severity and frequency of depressive episodes. Bipolar depression affords greater socio-economic burden than either mania and unipolar depression⁵ and represents the majority of symptomatic illness in bipolar affective disorder in respect to time.^6,7

The drug treatment of bipolar depression is somewhat controversial for two reasons. First, until recently there were few well-conducted, randomised, controlled trials specifically in bipolar depression and second, the condition entails consideration of lifelong outcome rather than simply discrete episode response.⁸ We have some knowledge of the therapeutic effects of drugs in bipolar depressive episodes but more limited awareness of the therapeutic or deleterious effects of drugs in the longer term. In the UK, NICE recommends the initial use of fluoxetine combined with olanzapine or quetiapine on its own (assuming an antipsychotic is not already prescribed).⁹ Lamotrigine is considered to be second-line treatment (although we consider the evidence for lamotrigine rather weak). Tables 3.8, 3.9 and 3.10 give some broad guidance on treatment options in bipolar depression.

Table 3.8 Established treatments for bipolar depression (listed in alphabetical order)

Table 3.9 Alternative drug treatments for bipolar depression

Table 3.10 Other possible treatments for bipolar depression

Meta-analysis in bipolar depression

Meta-analytic studies in bipolar depression are constrained by the variety of methods used to assess efficacy. This means that many scientifically robust studies cannot be included in some meta-analyses because their parameters (outcomes, duration, etc.) do not match, and so cannot be compared with other studies. Early lithium studies are an important example—their short duration and cross-over design precludes their inclusion in meta-analysis. A meta-analysis of five trials (906 participants) revealed that antidepressants were no better than placebo in respect to response or remission, although results approached statistical significance.⁷⁶ Another analysis of trials not involving antidepressants⁹⁸ (7,307 participants) found a statistical advantage over placebo for olanzapine + fluoxetine, valproate, quetiapine, lurasidone, olanzapine, aripiprazole and carbamazepine (in order of effect size, highest first).

The largest analysis is a multiple treatments meta-analysis of 29 studies including 8,331 subjects.⁹⁹ Overall olanzapine + fluoxetine, lurasidone, olanzapine, valproate, SSRIs and quetiapine were ranked highest in terms of effect size and response with olanzapine + fluoxetine ranked first for both.

Summary of drug choice

The combination of olanzapine + fluoxetine is probably the most effective treatment available for bipolar depression (other SSRIs may be effective but should be avoided unless clear individual benefit is obvious³⁶). Other first-line choices are quetiapine, olanzapine, lurasidone and valproate. These drugs differ substantially in adverse effect profile, tolerability and cost, each of which needs to be considered when prescribing for an individual. Lithium and lamotrigine are also effective but supporting evidence is relatively weak (although clinical experience is, in contrast, vast). Aripiprazole, risperidone, ziprasidone, tricyclics and MAOIs are probably not effective and should not be used.⁹⁹

References

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41. Goodwin FK et al. Suicide risk in bipolar disorder during treatment with lithium and divalproex. JAMA 2003; 290:1467–1473.
42. Kessing LV et al. Suicide risk in patients treated with lithium. Arch Gen Psychiatry 2005; 62:860–866.
43. Loebel A et al. Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry 2014; 171:160–168.
44. Loebel A et al. Lurasidone as adjunctive therapy with lithium or valproate for the treatment of bipolar I depression: a randomized, doubleblind, placebo-controlled study. Am J Psychiatry 2014; 171:169–177.
45. Tohen M et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry 2003; 60:1079–1088.
46. Brown EB et al. A 7-week, randomized, double-blind trial of olanzapine/fluoxetine combination versus lamotrigine in the treatment of bipolar I depression. J Clin Psychiatry 2006; 67:1025–1033.
47. Corya SA et al. A 24-week open-label extension study of olanzapine-fluoxetine combination and olanzapine monotherapy in the treatment of bipolar depression. J Clin Psychiatry 2006; 67:798–806.
48. Dube S et al. Onset of antidepressant effect of olanzapine and olanzapine/fluoxetine combination in bipolar depression. Bipolar Disord 2007; 9:618–627.
49. Tohen M et al. Randomised, double-blind, placebo-controlled study of olanzapine in patients with bipolar I depression. BrJPsychiatry 2012; 201:376–382.
50. Calabrese JR et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry 2005; 162:1351–1360.
51. Thase ME et al. Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebo-controlled study (the BOLDER II study). J Clin Psychopharmacol 2006; 26:600–609.
52. Suppes T et al. Effectiveness of the extended release formulation of quetiapine as monotherapy for the treatment of acute bipolar depression. J Affect Disord 2010; 121:106–115.
53. Young AH et al. A double-blind, placebo-controlled study of quetiapine and lithium monotherapy in adults in the acute phase of bipolar depression (EMBOLDEN I). J Clin Psychiatry 2010; 71:150–162.
54. McElroy SL et al. A double-blind, placebo-controlled study of quetiapine and paroxetine as monotherapy in adults with bipolar depression (EMBOLDEN II). J Clin Psychiatry 2010; 71:163–174.
55. Vieta E et al. Efficacy and safety of quetiapine in combination with lithium or divalproex for maintenance of patients with bipolar I disorder (international trial 126). J Affect Disord 2008; 109:251–263.
56. Suppes T et al. Maintenance treatment for patients with bipolar I disorder: results from a north american study of quetiapine in combination with lithium or divalproex (trial 127). Am J Psychiatry 2009; 166:476–488.
57. Goodwin GM. Evidence-based guidelines for treating bipolar disorder: revised second edition–recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2009; 23:346–388.
58. Davis LL et al. Divalproex in the treatment of bipolar depression: a placebo-controlled study. J Affect Disord 2005; 85:259–266.
59. Ghaemi SN et al. Divalproex in the treatment of acute bipolar depression: a preliminary double-blind, randomized, placebo-controlled pilot study. J Clin Psychiatry 2007; 68:1840–1844.
60. Smith LA et al. Valproate for the treatment of acute bipolar depression: systematic review and meta-analysis. J Affect Disord 2010; 122:1–9.
61. Muzina DJ et al. Acute efficacy of divalproex sodium versus placebo in mood stabilizer-naive bipolar I or II depression: a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry 2011; 72:813–819.
62. Amsterdam JD et al. Short-term fluoxetine monotherapy for bipolar type II or bipolar NOS major depression—low manic switch rate. Bipolar Disord 2004; 6:75–81.
63. Amsterdam JD et al. Efficacy and safety of fluoxetine in treating bipolar II major depressive episode. J Clin Psychopharmacol 1998; 18:435–440.
64. Amsterdam J. Efficacy and safety of venlafaxine in the treatment of bipolar II major depressive episode. J Clin Psychopharmacol 1998; 18:414–417.
65. Amsterda, JD et al. Venlafaxine monotherapy in women with bipolar II and unipolar major depression. J Affect Disord 2000; 59:225–229.
66. Silverstone T. Moclobemide vs. imipramine in bipolar depression: a multicentre double-blind clinical trial. Acta Psychiatr Scand 2001; 104:104–109.
67. Ghaemi SN et al. Antidepressant treatment in bipolar versus unipolar depression. Am J Psychiatry 2004; 161:163–165.
68. Post RM et al. A re-evaluation of the role of antidepressants in the treatment of bipolar depression: data from the Stanley Foundation Bipolar Network. Bipolar Disord 2003; 5:396–406.
69. Amsterdam JD et al. Comparison of fluoxetine, olanzapine, and combined fluoxetine plus olanzapine initial therapy of bipolar type I and type II major depression–lack of manic induction. J Affect Disord 2005; 87:121–130.
70. Amsterdam JD et al. Fluoxetine monotherapy of bipolar type II and bipolar NOS major depression: a double-blind, placebo-substitution, continuation study. Int Clin Psychopharmacol 2005; 20:257–264.
71. Dilsaver SC et al. Treatment of bipolar depression with carbamazepine: results of an open study. Biol Psychiatry 1996; 40:935–937.
72. Goldberg JF et al. Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatmentresistant bipolar depression. Am J Psychiatry 2004; 161:564–566.
73. Zarate CA, Jr. et al. Pramipexole for bipolar II depression: a placebo-controlled proof of concept study. Biol Psychiatry 2004; 56:54–60.
74. Ketter TA et al. Adjunctive aripiprazole in treatment-resistant bipolar depression. Ann Clin Psychiatry 2006; 18:169–172.
75. Mazza M et al. Beneficial acute antidepressant effects of aripiprazole as an adjunctive treatment or monotherapy in bipolar patients unresponsive to mood stabilizers: results from a 16-week open-label trial. Expert Opin Pharmacother 2008; 9:3145–3149.
76. Sidor MM et al. Antidepressants for the acute treatment of bipolar depression: a systematic review and meta-analysis. J Clin Psychiatry 2011; 72:156–167.
77. Cruz N et al. Efficacy of modern antipsychotics in placebo-controlled trials in bipolar depression: a meta-analysis. Int J Neuropsychopharmacol 2010; 13:5–14 .
78. Wang PW et al. Gabapentin augmentation therapy in bipolar depression. Bipolar Disord 2002; 4:296–301.
79. Ashton H et al. GABA-ergic drugs: exit stage left, enter stage right. J Psychopharmacol 2003; 17:174–178.
80. Chengappa KN et al. Inositol as an add-on treatment for bipolar depression. Bipolar Disord 2000; 2:47–55.
81. Diazgranados N et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry 2010; 67:793–802.
82. Shahani R et al. Ketamine-associated ulcerative cystitis: a new clinical entity. Urology 2007; 69:810–812.
83. Zarate CA, Jr. et al. Replication of ketamine's antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry 2012; 71:939–946.
84. Young AH et al. Improvements in neurocognitive function and mood following adjunctive treatment with mifepristone (RU-486) in bipolar disorder. Neuropsychopharmacology 2004; 29:1538–1545.
85. Watson S et al. A randomized trial to examine the effect of mifepristone on neuropsychological performance and mood in patients with bipolar depression. Biol Psychiatry 2012; 72:943–949.
86. Frye MA et al. A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression. Am J Psychiatry 2007; 164:1242–1249.
87. Calabrese JR et al. Adjunctive armodafinil for major depressive episodes associated with bipolar I disorder: a randomized, multicenter, double-blind, placebo-controlled, proof-of-concept study. J Clin Psychiatry 2010; 71:1363–1370.
88. Frangou S et al. Efficacy of ethyl-eicosapentaenoic acid in bipolar depression: randomised double-blind placebo-controlled study. Br J Psychiatry 2006; 188:46–50.
89. Keck PE, Jr. et al. Double-blind, randomized, placebo-controlled trials of ethyl-eicosapentanoate in the treatment of bipolar depression and rapid cycling bipolar disorder. Biol Psychiatry 2006; 60:1020–1022.
90. Singh J et al. Case report: Successful riluzole augmentation therapy in treatment-resistant bipolar depression following the development of rash with lamotrigine. Psychopharmacology (Berl) 2004; 173:227–228.
91. Brennan BP et al. Rapid enhancement of glutamatergic neurotransmission in bipolar depression following treatment with riluzole. Neuropsychopharmacology 2010; 35:834–846.
92. Bauer M. Thyroid hormone augmentation with levothyroxine in bipolar depression. Bipolar Disord 2002; 4 Suppl 1:109–110.
93. Stamm TJ et al. Supraphysiologic doses of levothyroxine as adjunctive therapy in bipolar depression: a randomized, double-blind, placebocontrolled study. J Clin Psychiatry 2014; 75:162–168.
94. Ghaemi SN et al. An open prospective study of zonisamide in acute bipolar depression. J Clin Psychopharmacol 2006; 26:385–388.
95. Anand A et al. A preliminary open-label study of zonisamide treatment for bipolar depression in 10 patients. J Clin Psychiatry 2005; 66:195–198.
96. Wilson MS et al. Zonisamide for bipolar depression. Expert Opin Pharmacother 2007; 8:111–113.
97. McElroy SL et al. Open-label adjunctive zonisamide in the treatment of bipolar disorders: a prospective trial. J Clin Psychiatry 2005; 66:617–624.
98. Selle V et al. Treatments for acute bipolar depression: meta-analyses of placebo-controlled, monotherapy trials of anticonvulsants, lithium and antipsychotics. Pharmacopsychiatry 2014; 47:43–52.
99. Taylor DM et al. Comparative efficacy and acceptability of drug treatments for bipolar depression: a multiple-treatments meta-analysis. Acta Psychiatr Scand 2014: in press.

Rapid-cycling bipolar affective disorder

Rapid cycling is usually defined as bipolar affective disorder in which four or more episodes of (hypo) mania or depression occur in a 12-month period. It is generally held to be less responsive to drug treatment than non-rapid-cycling bipolar illness^1,2 and entails considerable depressive morbidity and suicide risk.³ Table 3.11 outlines a treatment strategy for rapid cycling based on rather limited data and very few direct comparisons of drugs.^4,5 This strategy is broadly in line with the findings of a recent systematic review.⁵ NICE conclude that there is no evidence to support rapid-cycling illness being managed any differently from that with a more conventional course.⁶ Lithium, alone or in combination with valproate, would therefore be first-line treatment. An alternative would be to add an antipsychotic with proven activity in bipolar affective disorder and/or rapid cycling (see below).

In practice, response to treatment is sometimes idiosyncratic: individuals may show significant response only to one or two drugs. Spontaneous or treatment-related remissions occur in around one-third of rapid-cyclers⁷ and rapid cycling may come and go in most patients.⁸ Non-drug methods may also be considered.^9,10

Table 3.11 Recommended treatment strategy for rapid-cycling bipolar affective disorder

References

1. Calabrese JR et al. Current research on rapid cycling bipolar disorder and its treatment. J Affect Disord 2001; 67:241–255.
2. Kupka RW et al. Rapid and non-rapid cycling bipolar disorder: a meta-analysis of clinical studies. J Clin Psychiatry 2003; 64:1483–1494.
3. Coryell W et al. The long-term course of rapid-cycling bipolar disorder. Arch Gen Psychiatry 2003; 60:914–920.
4. Tondo L et al. Rapid-cycling bipolar disorder: effects of long-term treatments. Acta Psychiatr Scand 2003; 108:4–14 .
5. Fountoulakis KN et al. A systematic review of the evidence on the treatment of rapid cycling bipolar disorder. Bipolar Disord 2013; 15:115–137.
6. National Institute for Health and Care Excellence. Bipolar disorder: the assessment and management of bipolar disorder in adults, children and young people in primary and secondary care. Clinical Guidance 185, 2014. https://www.nice.org.uk/
7. Koukopoulos A et al. Duration and stability of the rapid-cycling course: a long-term personal follow-up of 109 patients. J Affect Disord 2003; 73:75–85.
8. Carvalho AF et al. Rapid cycling in bipolar disorder: a systematic review. J Clin Psychiatry 2014; 75:e578–586.
9. Dell'osso B et al. Augmentative transcranial magnetic stimulation (TMS) combined with brain navigation in drug-resistant rapid cycling bipolar depression: a case report of acute and maintenance efficacy. World J Biol Psychiatry 2009; 10:673–676.
10. Marangell LB et al. A 1-year pilot study of vagus nerve stimulation in treatment-resistant rapid-cycling bipolar disorder. J Clin Psychiatry 2008; 69:183–189.
11. Wehr TA et al. Can antidepressants cause mania and worsen the course of affective illness? Am J Psychiatry 1987; 144:1403–1411.
12. Altshuler LL et al. Antidepressant-induced mania and cycle acceleration: a controversy revisited. Am J Psychiatry 1995; 152:1130–1138.
13. Association AP. Practice guideline for the treatment of patients with bipolar disorder. Am J Psychiatry 2002; 159 Suppl 4:1–50.
14. Ghaemi SN et al. Antidepressant discontinuation in bipolar depression: a Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) randomized clinical trial of long-term effectiveness and safety. J Clin Psychiatry 2010; 71:372–380.
15. Ghaemi SN. Treatment of rapid-cycling bipolar disorder: are antidepressants mood destabilizers? Am J Psychiatry 2008; 165:300–302.
16. Amsterdam JD et al. Efficacy and mood conversion rate during long-term fluoxetine v. lithium monotherapy in rapidand non-rapid-cycling bipolar II disorder. Br J Psychiatry 2013; 202:301–306.
17. Amsterdam JD et al. Effectiveness and mood conversion rate of short-term fluoxetine monotherapy in patients with rapid cycling bipolar II depression versus patients with nonrapid cycling bipolar II depression. J Clin Psychopharmacol 2013; 33:420–424.
18. Sanger TM et al. Olanzapine in the acute treatment of bipolar I disorder with a history of rapid cycling. J Affect Disord 2003; 73:155–161.
19. Kemp DE et al. A 6-month, double-blind, maintenance trial of lithium monotherapy versus the combination of lithium and divalproex for rapid-cycling bipolar disorder and Co-occurring substance abuse or dependence. J Clin Psychiatry 2009; 70:113–121.
20. da Rocha FF et al. Addition of lamotrigine to valproic acid: a successful outcome in a case of rapid-cycling bipolar affective disorder. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31:1548–1549.
21. Woo YS et al. Lamotrigine added to valproate successfully treated a case of ultra-rapid cycling bipolar disorder. Psychiatry Clin Neurosci 2007; 61:130–131.
22. Calabrese JR et al. A 20-month, double-blind, maintenance trial of lithium versus divalproex in rapid-cycling bipolar disorder. Am J Psychiatry 2005; 162:2152–2161.
23. Suppes T et al. Efficacy and safety of aripiprazole in subpopulations with acute manic or mixed episodes of bipolar I disorder. J Affect Disord 2008; 107:145–154.
24. Muzina DJ et al. Aripiprazole monotherapy in patients with rapid-cycling bipolar I disorder: an analysis from a long-term, double-blind, placebo-controlled study. Int J Clin Pract 2008; 62:679–687.
25. Calabrese JR et al. Clozapine prophylaxis in rapid cycling bipolar disorder. J Clin Psychopharmacol 1991; 11:396–397.
26. Fatemi SH et al. Lamotrigine in rapid-cycling bipolar disorder. J Clin Psychiatry 1997; 58:522–527.
27. Calabrese JR et al. A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. Lamictal 614 Study Group. J Clin Psychiatry 2000; 61:841–850.
28. Wang Z et al. Lamotrigine adjunctive therapy to lithium and divalproex in depressed patients with rapid cycling bipolar disorder and a recent substance use disorder: a 12-week, double-blind, placebo-controlled pilot study. Psychopharmacol Bull 2010; 43:5–21.
29. Braunig P et al. Levetiracetam in the treatment of rapid cycling bipolar disorder. J Psychopharmacol 2003; 17:239–241.
30. Goodnick PJ. Nimodipine treatment of rapid cycling bipolar disorder. J Clin Psychiatry 1995; 56:330.
31. Pazzaglia PJ et al. Preliminary controlled trial of nimodipine in ultra-rapid cycling affective dysregulation. Psychiatry Res 1993; 49:257–272.
32. Goldberg JF et al. Effectiveness of quetiapine in rapid cycling bipolar disorder: a preliminary study. J Affect Disord 2008; 105:305–310.
33. Vieta E et al. Quetiapine monotherapy in the treatment of patients with bipolar I or II depression and a rapid-cycling disease course: a randomized, double-blind, placebo-controlled study. Bipolar Disord 2007; 9:413–425.
34. Langosch JM et al. Efficacy of quetiapine monotherapy in rapid-cycling bipolar disorder in comparison with sodium valproate. J Clin Psychopharmacol 2008; 28:555–560.
35. Vieta E et al. Quetiapine in the treatment of rapid cycling bipolar disorder. Bipolar Disord 2002; 4:335–340.
36. Jacobsen FM. Risperidone in the treatment of affective illness and obsessive-compulsive disorder. J Clin Psychiatry 1995; 56:423–429.
37. Bobo WV et al. A randomized open comparison of long-acting injectable risperidone and treatment as usual for prevention of relapse, rehospitalization, and urgent care referral in community-treated patients with rapid cycling bipolar disorder. Clin Neuropharmacol 2011; 34:224–233.
38. Vieta E et al. Treatment of refractory rapid cycling bipolar disorder with risperidone. J Clin Psychopharmacol 1998; 18:172–174.
39. Weeston TF et al. High-dose T4 for rapid-cycling bipolar disorder. J Am Acad Child Adolesc Psychiatry 1996; 35:131–132 .
40. Extein IL. High doses of levothyroxine for refractory rapid cycling. Am J Psychiatry 2000; 157:1704–1705.
41. Chen CK et al. Combination treatment of clozapine and topiramate in resistant rapid-cycling bipolar disorder. Clin Neuropharmacol 2005; 28:136–138.

Prophylaxis in bipolar affective disorder

The median duration of mood episodes in people with bipolar affective disorder has been reported to be 13 weeks, with a quarter of patients remaining unwell at 1 year.¹ Most people with bipolar affective disorder spend much more time depressed than manic,² and bipolar depression can be very difficult to treat. The suicide rate in bipolar illness is increased 25-fold over population norms and the vast majority of suicides occur during episodes of depression.³ Mixed states are also common and present an increased risk of suicide.⁴

Note that residual symptoms after an acute episode are a strong predictor of recurrence.^1,5 Most evidence supports the efficacy of lithium^6–10 in preventing episodes of mania and depression. Carbamazepine is somewhat less effective^10,11 and the long-term efficacy of valproate is uncertain,^8,9,12–14 although it too may protect against relapse both into depression and mania.^10,15 Lithium has the advantage of a proven anti-suicidal effect^16–18 but perhaps, relative to other mood stabilisers, the disadvantage of a worsened outcome following abrupt discontinuation.^19–22

The BALANCE study found that valproate as monotherapy was relatively less effective than lithium or the combination of lithium and valproate,¹³ casting doubt on its use as a first-line single treatment. Also, a large observational study has shown that lithium is much more effective than valproate in preventing relapse to any condition and in preventing rehospitalisation.²³ Given this and the fact that valproate is not licensed for prophylaxis, it should now be considered a second-line treatment.

Conventional antipsychotics have traditionally been used and are perceived to be effective although the objective evidence base is, again, weak.^24,25 FGA depots protect against mania but may worsen depression.²⁶ Evidence supports the efficacy of some SGAs, particularly olanzapine,^9,27 quetiapine,²⁸ aripiprazole²⁹ and risperidone.³⁰ Olanzapine, quetiapine and aripiprazole are licensed for prophylaxis and appear to protect against both mania and depression. Whether SGAs are more effective than FGAs, or are truly associated with a reduced overall side-effect burden, remains untested.

NICE recommendations²⁷

• When planning long-term pharmacological interventions to prevent relapse, take into account drugs that have been effective during episodes of mania or bipolar depression. Discuss with the person whether they prefer to continue this treatment or switch to lithium, and explain that lithium is the most effective long-term treatment for bipolar affective disorder.
• Offer lithium as a first-line, long-term pharmacological treatment for bipolar affective disorder and: if lithium is insufficiently effective, consider adding valproate; if lithium is poorly tolerated, consider valproate or olanzapine instead, or if it has been effective during an episode of mania or bipolar depression, quetiapine.
• Do not offer valproate to women of child-bearing age.
• Discuss with the person the possible benefits and risks of each drug for them.
• The secondary care team should maintain responsibility for monitoring the efficacy and tolerability of antipsychotic medication until the person's condition has stabilised.
• Before stopping medication, discuss with the person how to recognise early signs of relapse and what to do if symptoms recur.
• If stopping medication, do so gradually and monitor for signs of relapse.
• Continue monitoring symptoms, mood and mental state for 2 years after stopping medication. This may be undertaken in primary care.

A significant proportion of patients with bipolar illness fail to be treated adequately with a single mood-stabiliser,¹³ so combinations of mood-stabilisers^31,32 or a mood-stabiliser and an antipsychotic^32,33 are commonly used.³⁴ Also, there is evidence that where combination treatments are effective in mania or depression, then continuation with the same combination provides optimal prophylaxis.^28,33 The use of polypharmacy needs to be balanced against the likely increased side-effect burden. Combinations of olanzapine, risperidone, quetiapine or haloperidol with lithium or valproate are recommend by NICE.²⁷ Alternative antipsychotics are also options in combinations with lithium or valproate, particularly if these have been found to be effective during the treatment of an acute episode of mania or depression^28,35 Carbamazepine is considered to be third line. Lamotrigine may be useful in bipolar II disorder²⁷ but seems only to prevent recurrence of depression.³⁶ Extrapolation of currently available data suggests that lithium plus a SGA is probably the polypharmacy regimen of choice.

A meta-analysis of long-term antidepressant treatment found that the number needed to treat (NNT) to prevent a new episode of depression was larger than the number needed to harm (NNH) related to precipitating a new episode of mania.³⁷ The STEP-BD study found no significant benefit for continuing (compared with discontinuing) an antidepressant and worse outcomes in those with rapid-cycling illness.³⁸ There is thus essentially no support for long-term use of antidepressants in bipolar illness, although they continue to be widely used.

Substance misuse increases the risk of switching into mania.³⁹

Summary: prophylaxis in bipolar affective disorder

First line: lithium

Second line: valproate (NOT in women of child-bearing age), olanzapine, or quetiapine

Third line: alternative antipsychotic that has been effective during an acute episode, carbamazepine, lamotrigine

• Always maintain successful acute treatment regimens (e.g. mood stabiliser + antipsychotic) prophylaxis.
• Avoid long-term antidepressants.

References

1. Solomon DA et al. Longitudinal course of bipolar I disorder: duration of mood episodes. Arch Gen Psychiatry 2010; 67:339–347.
2. Judd LL et al. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry 2003; 60:261–269.
3. Rihmer Z. Suicide and Bipolar Disorder. In: Zarate C, Jr., Manji HK, eds. Bipolar Depression: Molecular Neurobiology, Clinical Diagnosis and Pharmacotherapy (Milestones in Drug Therapy). Switzerland: Birkhäuser Basel; 2009. pp. 47–58.
4. Houston JP et al. Reduced suicidal ideation in bipolar I disorder mixed-episode patients in a placebo-controlled trial of olanzapine combined with lithium or divalproex. J Clin Psychiatry 2006; 67:1246–1252.
5. Perlis RH et al. Predictors of recurrence in bipolar disorder: primary outcomes from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry 2006; 163:217–224.
6. Young AH et al. Lithium in mood disorders: increasing evidence base, declining use? Br J Psychiatry 2007; 191:474–476.
7. Biel MG et al. Continuation versus discontinuation of lithium in recurrent bipolar illness: a naturalistic study. Bipolar Disord 2007; 9: 435–442.
8. Bowden CL et al. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group. Arch Gen Psychiatry 2000; 57:481–489.
9. Tohen M et al. Olanzapine versus divalproex sodium for the treatment of acute mania and maintenance of remission: a 47-week study. Am J Psychiatry 2003; 160:1263–1271.
10. Goodwin G. Evidence-based guidelines for treating bipolar disorder: revised second edition–recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2009; 23:346–388.
11. Hartong EG et al. Prophylactic efficacy of lithium versus carbamazepine in treatment-naive bipolar patients. J Clin Psychiatry 2003; 64:144–151.
12. Cipriani A et al. Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder. Cochrane Database Syst Rev 2013; 10: CD003196.
13. Geddes JR et al. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet 2010; 375:385–395.
14. Kemp DE et al. A 6-month, double-blind, maintenance trial of lithium monotherapy versus the combination of lithium and divalproex for rapid-cycling bipolar disorder and Co-occurring substance abuse or dependence. J Clin Psychiatry 2009; 70:113–121.
15. Smith LA et al. Effectiveness of mood stabilizers and antipsychotics in the maintenance phase of bipolar disorder: a systematic review of randomized controlled trials. Bipolar Disord 2007; 9:394–412.
16. Cipriani A et al. Lithium in the prevention of suicidal behavior and all-cause mortality in patients with mood disorders: a systematic review of randomized trials. Am J Psychiatry 2005; 162:1805–1819.
17. Kessing LV et al. Suicide risk in patients treated with lithium. Arch Gen Psychiatry 2005; 62:860–866.
18. Young AH et al. Lithium in maintenance therapy for bipolar disorder. J Psychopharmacol 2006; 20:17–22.
19. Mander AJ et al. Rapid recurrence of mania following abrupt discontinuation of lithium. Lancet 1988; 2:15–17.
20. Faedda GL et al. Outcome after rapid vs gradual discontinuation of lithium treatment in bipolar disorders. Arch Gen Psychiatry 1993; 50:448–455.
21. Macritchie KA et al. Does 'rebound mania' occur after stopping carbamazepine? A pilot study. J Psychopharmacol 2000; 14:266–268.
22. Franks MA et al. Bouncing back: is the bipolar rebound phenomenon peculiar to lithium? A retrospective naturalistic study. J Psychopharmacol 2008; 22:452–456.
23. Kessing LV et al. Valproate v. lithium in the treatment of bipolar disorder in clinical practice: observational nationwide register-based cohort study. Br J Psychiatry 2011; 199:57–63.
24. Gao K et al. Typical and atypical antipsychotics in bipolar depression. J Clin Psychiatry 2005; 66:1376–1385.
25. Hellewell JS. A review of the evidence for the use of antipsychotics in the maintenance treatment of bipolar disorders. J Psychopharmacol 2006; 20:39–45.
26. Gigante AD et al. Long-acting injectable antipsychotics for the maintenance treatment of bipolar disorder. CNS Drugs 2012; 26:403–420.
27. National Institute for Health and Care Excellence. Bipolar disorder: the assessment and management of bipolar disorder in adults, children and young people in primary and secondary care. Draft for consultation, April 2014. https://www.nice.org.uk/
28. Vieta E et al. Efficacy and safety of quetiapine in combination with lithium or divalproex for maintenance of patients with bipolar I disorder (international trial 126). J Affect Disord 2008; 109:251–263.
29. McIntyre RS. Aripiprazole for the maintenance treatment of bipolar I disorder: A review. Clin Ther 2010; 32 Suppl 1:S32–S38.
30. Ghaemi SN et al. Long-term risperidone treatment in bipolar disorder: 6-month follow up. Int Clin Psychopharmacol 1997; 12:333–338.
31. Freeman MP et al. Mood stabilizer combinations: a review of safety and efficacy. Am J Psychiatry 1998; 155:12–21.
32. Muzina DJ et al. Maintenance therapies in bipolar disorder: focus on randomized controlled trials. Aust N Z J Psychiatry 2005; 39:652–661.
33. Tohen M et al. Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabiliser v. mood stabiliser alone. Br J Psychiatry 2004; 184:337–345.
34. Paton C et al. Lithium in bipolar and other affective disorders: prescribing practice in the UK. J Psychopharmacol 2010; 24:1739–1746.
35. Marcus R et al. Efficacy of aripiprazole adjunctive to lithium or valproate in the long-term treatment of patients with bipolar I disorder with an inadequate response to lithium or valproate monotherapy: a multicenter, double-blind, randomized study. Bipolar Disord 2011; 13:133–144.
36. Bowden CL et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry 2003; 60:392–400.
37. Ghaemi SN et al. Long-term antidepressant treatment in bipolar disorder: meta-analyses of benefits and risks. Acta Psychiatr Scand 2008; 118:347–356.
38. Ghaemi SN et al. Antidepressant discontinuation in bipolar depression: a Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) randomized clinical trial of long-term effectiveness and safety. J Clin Psychiatry 2010; 71:372–380.
39. Ostacher MJ et al. Impact of substance use disorders on recovery from episodes of depression in bipolar disorder patients: prospective data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry 2010; 167:289–297.

Physical monitoring for people with bipolar affective disorder

Table 3.12 Physical monitoring for people with bipolar affective disorder*

References

1. National Institute for Health and Care Excellence. Bipolar disorder: the assessment and management of bipolar disorder in adults, children and young people in primary and secondary care. Clinical Guideline 185, 2014. https://www.nice.org.uk/
2. National Patient Safety Agency. Safer lithium therapy. NPSA/2009/PSA005, 2009. http://www.nrls.npsa.nhs.uk/