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British Medical Bulletin 57:179-192 (2001)
© 2001 Oxford University Press
Developments in mood stabilisers
Depression and public health
Department of Psychiatry, University of Newcastle upon Tyne, Newcastle upon Tyne, UK
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Abstract |
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 TopFootnotes Abstract IntroductionLithiumNewer mood stabilisers -...Issues related to prescribing...Other pharmacological and non...ConclusionsKey points for clinical...References |
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Bipolar affective disorder is a life-long condition with profound effects on sufferers' social and occupational life. Despite efficacy in clinical trials and in some groups of patients, lithium's effectiveness in clinical practice is hampered by its side effect profile and limited concordance. Alternative and adjunctive treatments to lithium in bipolar disorder have been sought and the anticonvulsants carbamazepine and valproate show promise. Despite these advances, treatment resistance persists. Lamotrigine, a new anticonvulsant, is increasingly used in treatment-resistant cases under specialist supervision. Further pharmacological and non-pharmacological strategies for bipolar prophylaxis are currently under investigation. These developments are the focus of this review.
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Introduction |
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TopFootnotesAbstractIntroductionLithiumNewer mood stabilisers -...Issues related to prescribing...Other pharmacological and non...ConclusionsKey points for clinical...References |
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Classically, bipolar disorder takes the form of repeated periods of mania, hypomania or depression with full inter-episode recovery. However, in practice, approximately one-third of patients suffer chronic symptoms1
and persistent psychosocial difficulties are common2. Amongst mental illnesses, bipolar disorder is ranked second only to unipolar depression as a cause of world-wide disability3. Over the past decade, there have been many advances in the pharmacological and psychological treatment of this disorder which are the subject of this article.
The lifetime risk of bipolar disorder is 1.2%, increasing to 10% in first-degree relatives. Prevalence does not differ with sex, but is higher in urban areas4. Of the 1845 patients on the average general practitioner's list in the UK5, 22 will develop bipolar disorder at some point in their lives. Bipolar disorder may go unrecognised in a substantial number of patients.
Mania is characterised by elated mood accompanied by over-activity, pressure of speech and disturbed sleep. There is increased speed of thought and activity until efficiency is compromised by poor concentration. Irritability may occur rather than elation. Patients may experience hallucinations and mood-congruent delusions. Disinhibition, impractical and extravagant plans and grandiose ideas may result in grave consequences for an individual's professional life, social functioning and financial stability. In hypomania, these symptoms are less severe and there are no psychotic symptoms. Depressive episodes are manifest in low mood, loss of interest and enjoyment, diminished energy, poor concentration, disturbed sleep and appetite. Self-esteem and confidence are low and ideas of guilt, hopelessness and suicide may occur. Psychotic symptoms may feature in severe episodes. Episodes of mania and depression may happen in isolation or follow in quick succession. Poor prognostic indicators in bipolar disorder include the development of rapid-cycling disorder, where four or more episodes occur within a year, and mixed states, where manic and depressive symptoms are experienced together.
Mood stabilisers have become the cornerstone of pharmacological treatment of bipolar disorder. An ideal mood stabiliser should both treat episodes of mania and depression and be effective in prophylaxis. It should not precipitate mania or depression, nor should it induce rapid cycling disorder.
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Lithium |
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TopFootnotesAbstractIntroductionLithiumNewer mood stabilisers -...Issues related to prescribing...Other pharmacological and non...ConclusionsKey points for clinical...References |
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Lithium has been used in the treatment of bipolar disorder for the past 50 years Although it continues as a first-line treatment, approximately one-third of bipolar patients do not respond satisfactorily to this treatment6
, especially those with rapid cycling disorder and mixed episodes. Because of its narrow therapeutic window, frequent blood monitoring is required. Lithium is often associated with side effects, even at therapeutic levels. Fine tremor can be troublesome and is hard to manage – dose reduction is generally ineffective and ß blockade only partially effective. Despite controversy, it now seems clear that chronic use of lithium even with adequate blood level control can be associated with loss of renal glomerular function. Persistent polyuria is also troublesome and can worsen the risk of dehydration which, alone or in association with other causes, can lead to neurotoxicity which may be irreversible. Goitre and transient hypothyroidism occur commonly at the onset of treatment and a significant percentage of patients (2–3%) – predominantly female (90%) – will develop hypothyroidism on treatment. It is recognised that neurotoxicity can occur at therapeutic levels leading to the maxim that one should watch and listen to the patient, not just the blood level. For a fuller review of the current use and side-effect burden of lithium readers are referred elsewhere.7
In addition to (and probably because of) these difficulties, compliance is often poor: the median length of continuous use of lithium in one naturalistic study of a sub-group of patients with bipolar disorder was only 65 days8. Non-compliance is particularly problematic because lithium discontinuation may precipitate manic recurrence9,10. Women planning pregnancy face the possibility of developing mania on stopping this potentially teratogenic medication. The risk of lithium ‘rebound mania’ is lessened by its gradual withdrawal over a 15–30 day period11. Concerns that lithium withdrawal may result in subsequent resistance to its prophylactic effect have not been substantiated12. In summary, of all the agents used as mood stabilisers currently, lithium has the strongest evidence base. However, its effectiveness is limited by adverse effects, a narrow therapeutic window and non-compliance.
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Newer mood stabilisers – the anticonvulsants |
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TopFootnotesAbstractIntroductionLithiumNewer mood stabilisers -...Issues related to prescribing...Other pharmacological and non...ConclusionsKey points for clinical...References |
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Over the past 10 years, better mood stabilising treatments have been sought. The anticonvulsants valproate and carbamazepine are now established as alternative and adjunctive treatments to lithium. Carbamazepine is the only anticonvulsant licensed for use in bipolar disorder in the UK. However, valproate is the most frequently prescribed mood stabiliser in the US and is used increasingly in Europe. In January, 2001, ‘Depakote’ (valproate semi-sodium) was licensed for the treatment of acute mania in the UK.
Despite these developments, treatment resistance persists. In particular, bipolar depression remains a therapeutic problem: lithium, valproate and carbamazepine are more effective in treating and preventing mania than depression. Rapid-cycling disorder and mixed mania still challenge the clinician. Recently, the new anticonvulsants have been studied as potential mood stabilisers in the hope of finding more effective treatments. Of these, lamotrigine appears to have the largest evidence base in the form of randomised controlled trials (RCTs). Aspects of carbamazepine, valproate and lamotrigine treatment are now considered in detail, and brief accounts of some other emerging treatments are included.
Carbamazepine
Although carbamazepine has efficacy in treating mania, demonstrated in RCTs, the evidence for its antidepressive and prophylactic efficacy is not strong. Comparator trials against lithium have produced conflicting results13. Some authors have suggested that the efficacy of carbamazepine may fade with longer term treatment14. Most authorities suggest that carbamazepine is best used in combination with lithium15.
Side effects of carbamazepine include blurred vision, dizziness, ataxia and gastrointestinal disturbance. These effects are reversible and dose-related but often occur at doses used in bipolar disorder. Rash commonly occurs and treatment should be withdrawn if it persists or worsens. Carbamazepine can precipitate Stevens-Johnson syndrome and toxic epidermal necrolysis, and therapy should be stopped immediately if a patient develops mucocutaneous blisters or epidermal erosions with unexplained fever. Urgent dermatological advice should be sought and renal, hepatic and clotting function should be monitored16.
Carbamazepine is metabolised through the liver enzyme cytochrome P450. Carbamazepine induces the 3A4 isoform of this enzyme, thus enhancing its own metabolism. Its use may reduce the effectiveness of other drugs metabolised through the same system including other anticonvulsants, hormonal contraceptives and neuroleptics. The teratogenic effects of carbamazepine are discussed below. It is, therefore, particularly important that effective contraceptive measures are taken, and higher doses of hormonal contraceptives or alternative methods of birth control should be used. Some SSRIs and nefazodone may slow the metabolism of carbamazepine through inhibition of cytochrome P450 3A4, potentially precipitating toxic effects17.
Because of doubts regarding its efficacy, problems relating to its side effect profile and its interactions with other medications, carbamazepine is falling out of favour with most specialists prescribing for bipolar disorder.
Valproate
The efficacy of valproate in the treatment of mania has been established through RCTs and it has particular efficacy in dysphoric or mixed mania18. However, there are no such trials examining its efficacy in bipolar depression. Despite its widespread use, particularly in the US, its use in prophylaxis is based on open studies. The only RCT19 with bipolar patients reported valproate's prophylactic efficacy on some measures over a 12-month period. However, the significance of this result is questionable because of methodological limitations, and there is a need for further studies. Currently, a large randomised controlled study, the Balance Trial, is being planned aiming to recruit up to 2000 bipolar patients throughout the UK. This study will compare the prophylactic efficacy of lithium with that of valproate and combination treatment. It is hoped that this, one of the first trials of its size in psychiatry, will provide reliable evidence on which to base decisions on prophylactic treatment.
Valproate is generally well-tolerated. The commonest side effects are gastric irritation, nausea, ataxia and tremor. Increased appetite and weight gain can be problematic. The development of curly scalp hair and hair loss are rare occurrences. Most serious side effects can be avoided by a slow increase in dose. Rarely, non-dose-related severe hepatic damage can occur within the first six months of treatment. Valproate treatment is contra-indicated in those with active liver disease or a family history of hepatic dysfunction. Liver function should be monitored as described below. Rarely, valproate has been associated with acute pancreatitis. The polycystic ovarian syndrome has been reported in epileptic patients, but this has not been replicated in bipolar patients20.
Valproate competes with some anticonvulsants such as carbamazepine and lamotrigine for hepatic drug-metabolising enzymes, raising their plasma levels. It may enhance the anticoagulant effects of warfarin.
In summary, valproate is increasingly frequently prescribed for bipolar disorder and is the leading mood stabiliser in the US. Its effects against mania are established, but its antidepressant and prophylactic effects remain unproven. It has fewer problematic drug interactions than carbamazepine.
Lamotrigine
Lamotrigine is licensed as an adjunctive therapy for complex partial and generalised tonic-clonic seizures. Recently, controlled trials have been conducted on its use in mania21, bipolar depression22,23 and rapid-cycling disorder24. Although this research supports its efficacy in bipolar disorder (at doses of 50 mg and 200 mg), it remains unlicensed for this purpose. It should be reserved for cases of treatment resistance or for those intolerant to more conventional treatments.
The commonest adverse effects associated with the use of lamotrigine are headache, nausea, diplopia, dizziness and ataxia; sedation occurs occasionally. However, the main concern is a skin rash which occurs in 5% of patients, usually early in treatment: risk factors are polypharmacy, particularly with valproate and rapid dose increments. Children are particularly at risk. Usually, the rash is mild and abates independent of treatment withdrawal. However, occasionally serious generalised illnesses such as erythema multiforme, angio-oedema and Stevens-Johnson syndrome occur and fatalities have been reported. Renal, hepatic and clotting function should be monitored if a rash or influenza-type symptoms develop and treatment should be withdrawn immediately unless the rash is clearly not drug related. In epilepsy, lamotrigine has been safely re-introduced at a very slow rate in patients who have had a mild rash on first introduction25.
Lamotrigine does not induce cytochrome P450 enzymes and has no effects on other psychotropic medications. Carbamazepine induces lamotrigine metabolism. This combination has been reported to have neurotoxic effects through a pharmacodynamic interaction26. As discussed above, valproate potentially enhances the toxic effects of lamotrigine by impairing its elimination.
There is growing evidence supporting the mood stabilising effects of lamotrigine. Its efficacy in areas of treatment resistance such as bipolar depression and rapid-cycling disorder make it a welcome addition to the pharmacological armoury. However, it remains unlicensed for bipolar disorder and should be prescribed for treatment resistant cases under specialist supervision.
Gabapentin
Gabapentin is an anti-epileptic agent structurally related to 
-aminobutyric acid (GABA) with an unknown mechanism of action. It is in current use as augmentation therapy in patients with partial seizures resistant to conventional therapies. Gabapentin is not metabolised in humans. It is not protein bound. It has no known pharmacokinetic interactions with valproic acid, carbamazepine, other anticonvulsants or oral contraceptives and is excreted unchanged. Gabapentin has a high therapeutic index and a relatively benign side effect profile. Side effects reported with gabapentin are transient and minor, the most common being somnolence, dizziness, ataxia and fatigue27. It is not associated with hepatic or haematological problems. It has a wide dose range 900–3000 mg/day. Gabapentin's use in rapid cycling bipolar disorder, mania and bipolar depression is supported by open trials28–30. These findings have not been replicated in RCTs, two of which have been negative23,31.
Topiramate
Topiramate is a new anti-epileptic drug which is used as adjunctive therapy for partial seizures. It enhances GABA activity and blocks glutamate at non N-methyl D-aspartate (NMDA) receptors. Preliminary open observations of adjunctive topiramate treatment suggest that it may have antimanic or anticycling effects in some patients with bipolar disorder including those who are treatment resistant and it may be associated with appetite suppression and weight loss32–34. There is one case report of topiramate monotherapy in maintenance treatment of bipolar disorder35. RCTs are underway.
Tiagabine
There has been recent interest in the novel anticonvulsant, tiagabine, which reduces the re-uptake of GABA into neuronal and glial cells. Preliminary case reports have yielded conflicting results. The most promising reports use doses much lower than those typical for the treatment of seizures36–38.
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Issues related to prescribing anticonvulsants as mood stabilisers |
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TopFootnotesAbstractIntroductionLithiumNewer mood stabilisers -...Issues related to prescribing...Other pharmacological and non...ConclusionsKey points for clinical...References |
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Mechanisms of anticonvulsant action in bipolar affective disorder The mechanisms underlying the mood stabilising properties of anticonvulsants are poorly understood. It is unclear whether their mood-stabilising and anticonvulsant properties result from the same pharmacological effects. The GABA-mediated inhibitory effects of carbamazepine and valproate may play a central role in their therapeutic effect. Lamotrigine may act through the reduction of glutamate-stimulated excitatory processes and the modulation of signal transduction through its effects on membrane cation conductance. Clinical effects may also be mediated by a direct effect on central monoamines and through second messenger systems linked to the central actions of catecholamines39
. Combination treatments Combination treatments may be more effective than monotherapy, but they require further study in the form of RCTs. Combination treatments may increase the likelihood of side effects and toxicity.
Blood monitoring
The therapeutic serum levels for anticonvulsants in bipolar disorder have not been firmly established. There is little evidence for a direct relationship between anticonvulsant blood levels and efficacy in treatment of acute episodes or in the prophylactic treatment of bipolar affective disorder. One study of 65 manic patients using valproate suggested that levels above 45 mg/l were necessary for its antimanic effect40. From retrospective open studies, the optimum blood level for prophylaxis appears to be 60–90 mg/l, with 100–120 mg/l in difficult-to-treat cases and a high side effect burden is likely at > 125 mg/l41.
Blood disorders can occur with carbamazepine, and so regular full blood count monitoring is required during therapy. Liver function should be monitored prior to commencing valproate treatment and regularly thereafter, especially in the first 6 months of treatment. Mild elevation of hepatic enzymes requires further monitoring. Valproate should be withdrawn immediately if there is evidence of hepatic failure or severe oedema. Lamotrigine does not require regular monitoring, though a baseline full blood count, renal function and liver function tests should be undertaken.
Teratogenesis Teratogenicity is a major concern when considering the use of any medication in long-term prophylactics. There is an increased risk of teratogenicity associated with the use of anticonvulsant medication. Much of the data available on teratogenicity are on patients with epilepsy, a condition which itself has an increased incidence of developmental disorders. The risk of teratogenicity in non-epileptic patients remains unclear.
Neural tube defects are associated with the first trimester use of the folate antagonists carbamazepine and valproate. One study reported a reduction in the incidence of first occurrence and recurrence of neural tube defects in women with epilepsy receiving carbamazepine or valproate with folic acid supplementation prior to conception42. Maternal carbamazepine treatment may result in bleeding disorders in the new-born. Valproate has been reported to cause congenital anomalies, digit anomalies, oral clefts and orofacial dysmorphic features16. Lamotrigine is a weak folate antagonist with theoretical teratogenic potential. The Glaxo-Wellcome prospective pregnancy registry reported an unspecified birth defect rate of 8 among 149 patients exposed to lamotrigine (in combination therapy). All occurred with first trimester exposure; there were no reports of defects in pregnancies with exposure in the second and third trimesters of pregnancy43.
Given the teratogenic risks of anticonvulsant treatment particularly during the period of neural tube formation in the first trimester, pregnancy should be planned. The risks and benefits of on-going treatment should be carefully weighed. Withdrawal of treatment should be undertaken prior to conception. If anticonvulsant treatment is continued into pregnancy, then folate supplementation should be prescribed in the first trimester although its benefits are not firmly established.
Rebound phenomena
In contrast to lithium, there is little evidence regarding the existence of rebound mania on withdrawal of anticonvulsants. One case series examining the effects of carbamazepine withdrawal in bipolar patients did not support a rebound effect44. Anticonvulsant mood stabilisers may be a better choice for patients who are poorly compliant with medication but, as yet, there is insufficient evidence to recommend a change to prescribing practice.
Effects on suicide rate
It is estimated that 25–50% of bipolar patients attempt suicide at least once45. The recognised life-time risk of completed suicide is 15%, but this may be an over-estimate. Young men, early in the course of their illness, are at highest risk, especially those with a history of suicide attempts or alcohol misuse, and those recently discharged from hospital46. Lithium is thought to have direct anti-suicidal effects46; there is little information on the effects of anticonvulsants in reducing suicide rates.
Bipolar depression
The depressive phase of bipolar disorder is associated with considerable morbidity and mortality. Some treatments may precipitate mania and increase cycle frequency47. In general terms, the best strategies are to optimise mood stabiliser medication48 and to use antidepressants less likely to induce hypomania49 (e.g. SSRIs rather than tricyclics) and to avoid prolonged and high dose use. It is not yet clear if the anticonvulsants are more or less efficacious than lithium in the management of bipolar depression.
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Other pharmacological and non-pharmacological developments in the management of bipolar disorder |
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TopFootnotesAbstractIntroductionLithiumNewer mood stabilisers -...Issues related to prescribing...Other pharmacological and non...ConclusionsKey points for clinical...References |
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Antipsychotics Although typical antipsychotics are used frequently in the treatment of mania, they may worsen postmanic depression. Their prophylactic use risks the induction of tardive dyskinesia. Recently, the role of atypical antipsychotic medications has been investigated in bipolar disorder. Olanzapine is newly licensed in the US for the treatment of acute mania, and other atypical antipsychotics such as risperidone have also shown anti-manic efficacy in randomised controlled trials. Further research on atypical antipsychotic medication in bipolar depression and in prophylaxis is underway50
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Electroconvulsive therapy (ECT)
ECT is an effective treatment of bipolar disorder51. A 50-year review suggests that 66% of manic patients respond to ECT52. Furthermore, there is a good response to ECT in manic patients who have failed to respond to an antipsychotic or lithium53. Analysis of sequential therapeutic trials conducted over a 16-year period suggests that ECT followed by lithium maintenance is superior in efficacy to treatment with lithium or antipsychotics in hospitalised manic patients54. Maintenance or continuation ECT has been shown to reduce the incidence of relapse in patients with previously refractory depressive episodes55.
Transcranial magnetic stimulation (TMS)
There is preliminary open evidence of therapeutic efficacy of TMS in bipolar disorder56,57. However, there are also reports of hypomania induced by TMS58,59.
Thyroid hormones
The role of thyroid hormones in bipolar disorder continues to be investigated. Low levels of thyroxine (T4) have been associated with more affective episodes during maintenance treatment with lithium60. Whether this mood instability is causally related to low free T4 levels and whether it can be attenuated with thyroxine replacement remain to be studied in a controlled setting. Open trials suggest efficacy for thyroxine as an augmenting agent in resistant bipolar depression and rapid cycling disorder61,62.
Psycho-education and psychological treatments
Psycho-education and psychological treatments may be used to encourage healthy life-styles, to enhance coping strategies, to target early warning symptoms, to enhance compliance with medication and to address the psychosocial difficulties associated with the illness2. A recent RCT63 examined the efficacy of bipolar patients' learning to identify early symptoms of recurrence and to seek help. These patients experienced delays in the onset of manic, but not depressive, episodes. Improvements in social functioning and employment were also reported. Patients with bipolar disorder in remission have higher levels of cognitive vulnerability to depression than healthy subjects, a possible target for psychological treatments64. Preliminary results of controlled trials of cognitive therapy for established bipolar depression are encouraging65.
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Conclusions |
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TopFootnotesAbstractIntroductionLithiumNewer mood stabilisers -...Issues related to prescribing...Other pharmacological and non...ConclusionsKey points for clinical...References |
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Bipolar affective disorder is a life-long condition with profound effects on sufferers' social and occupational life. Carbamazepine and valproate have become established as alternative and adjunctive treatments to lithium therapy. Despite these advances, treatment resistance in bipolar disorder persists. Of the newer anticonvulsants, lamotrigine has the largest evidence base for its mood stabilising effects. In particular, it appears to be efficacious in bipolar depression and rapid-cycling disorder, two areas in which treatment has proved difficult in the past. Further pharmacological and non-pharmacological developments are currently under investigation and hopes are high that this increased research activity will not only identify effective treatments but also lead to the development of early and specific predictors of response to individual treatments.
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Key points for clinical practice |
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TopFootnotesAbstractIntroductionLithiumNewer mood stabilisers -...Issues related to prescribing...Other pharmacological and non...ConclusionsKey points for clinical...References |
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For prophylaxis of bipolar disorder:
- Lithium is best reserved for those with the classical form of the illness who are likely to be compliant. Non-compliance with lithium is a common and significant clinical problem
- The efficacy of carbamazepine in prophylaxis is not well established and its pharmacology leads to the need for careful vigilance for side effects and interactions with other drugs
- Valproate is the drug of choice in practice but the evidence base for its use is low. Monitoring for non-efficacy and side effects is necessary
- A variety of other drugs are in the process of evaluation and are best reserved for specialist use until further information is to hand
- All bipolar patients would benefit from psychosocial support and psycho-education. Specific forms of psychotherapy may be very helpful for selected cases
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Footnotes |
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TopFootnotesAbstractIntroductionLithiumNewer mood stabilisers -...Issues related to prescribing...Other pharmacological and non...ConclusionsKey points for clinical...References |
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Correspondence to: Prof. I Nicol Ferrier, Department of Psychiatry, University of Newcastle upon Tyne, Newcastle upon Tyne NE1 4LP, UK
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TopFootnotesAbstractIntroductionLithiumNewer mood stabilisers -...Issues related to prescribing...Other pharmacological and non...ConclusionsKey points for clinical...References |
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