Issuu on Google+

ADVANCES Bipolar disorder Issue 1 – March 2009


Introduction Welcome to the first issue of MIMS Advances in Bipolar Disorder, which focuses on some of the key areas influencing clinical practice in the UK today. In recent years, a number of ­second-generation antipsychotics previously only licensed for schizophrenia have been licensed as mood stabilisers, providing a valuable addition to the bipolar armamentarium. The challenges of prescribing these drugs in bipolar disorder, with their dosing variations and differing propensities to cause side-effects, are starting to be recognised in the prescribing guidelines. Ruth Ohlsen and Katherine Aitchison provide an overview of current UK guidance, including a look at monitoring requirements and special prescribing considerations. The excess burden of physical comorbidity in people with schizophrenia has long been recognised, and now there is growing evidence to suggest that this burden also extends to those with a diagnosis of bipolar disorder. Helen Millar looks at the causes of increased physical ill health in this patient group, and the importance of involving patients in decisions regarding their treatment. Management considerations for reducing metabolic and cardiovascular risk are discussed. In the final article of this issue, David Yeomans describes the rationale behind switching medications in bipolar disorder, explaining when and how it should be carried out. What to do in the instance of a failed switching attempt is also discussed. Dr Yeomans then presents a case study of a woman who was switched to aripiprazole treatment in order to reduce the side-effects she was experiencing with her existing therapy. Becki Davies

2 Use of aripiprazole and the bipolar disorder guidelines

Ruth Ohlsen and Katherine Aitchison Institute of Psychiatry, King’s College London

6 Patient choice and physical health in bipolar disorder

Helen Millar Carseview Centre, Dundee

9 Switching medications for bipolar disorder treatment

David Yeomans University of Leeds

Publisher: Haymarket Medical Imprint, 174 Hammersmith Road, London W6 7JP. Tel: 020 8267 4572. Email: Managing editor: Bettina Vine; Project editor: Becki Davies; Sub-editors: Gina Lyons, Philip MacDonald; Senior account manager: Lauren Meade; Senior production controller: Nicola Goodman; Group production manager: Philip Root; Group art editor: Pauline Lock; Editor-in-chief: Colin Cooper; Online publisher: Richard Yarwood; Managing director: Peter Welland. The views expressed on this publication are those of the authors and not necessarily those of Medical Imprint, BristolMyers Squibb or Otsuka. Readers are advised to make their own further enquiries of manufacturers or specialists in relation to particular drugs, treatments or advice. The publishers and printers cannot accept liability for errors or omissions. No part of this publication may be reproduced in any form without the written permission of the publisher, application for which should be made to the publisher. Front cover image: iStockphoto. ©2009 Haymarket Medical Media Ltd. Not for resale. Date of Haymarket is certified by BSI preparation March 2009. Item to environmental standard ISO14001 code: ABI/0908/3309/0810.

Commissioned and funded by Bristol-Myers Squibb/Otsuka Pharmaceuticals (UK) Ltd

Bipolar disorder

Use of aripiprazole and the bipolar disorder guidelines Ruth Ohlsen and Katherine Aitchison review current guidelines for bipolar disorder and discuss their implications for aripiprazole use in clinical practice The mainstay of treatment for bipolar disorder remains mood stabilisers. Although first-generation anti­ psychotics (FGAs) have for many years been combined with mood stabilisers, their use pre-dated more rigorous regulations on the use and licensing of medications. In the past five years, a number of second generation antipsychotics (SGAs) – previously only licensed for schizophrenia – have been licensed as mood stabilisers and/or for the treatment of various symptom dimensions in bipolar affective disorder. Prescribing guidelines are now reflecting this. Prescribing antipsychotics for bipolar disorder can be challenging because of their varying propensities to cause ADRs (see Table 1).1 Dosing of SGAs may differ between schizophrenia and bipolar disorder: those with the latter requiring higher doses in severe mania, but for maintenance possibly requiring lower doses.

Guidance on prescribing in bipolar disorder Current practical prescribing consensus guidelines for schizophrenia2 recommend commencing aripiprazole at 10mg, a lower dose than that recommended for initiation in bipolar patients (15mg).3 A consensus statement has been written regarding the use of aripiprazole for the treatment of bipolar disorder in the UK.4 When switching a patient to aripiprazole, care should be taken to ensure that therapeutic cover is maintained throughout the switching process. We suggest retaining the original antipsychotic until the patient is stabilised on aripiprazole. A short-term benzodiazepine or other ‘as needed’ medication may be added until the patient is stabilised on their minimum effective dose of aripiprazole. Once stabilised, a gradual taper down of

Key prescribing recommendations for bipolar disorder10

P Valproate should not routinely be prescribed for women of childbearing age.

P Lithium, olanzapine or valproate should be considered for long-term treatment.

P If monotherapy with any of these agents proves ineffective, then one of these agents should be used to augment treatment.

P If a trial of these agents proves ineffective, consider adding carbamazepine or lamotrigine (the latter particularly for bipolar depression).

P Quetiapine should be titrated up slowly to prevent orthostatic hypotension.

P Prolactin levels should be monitored in patients taking risperidone.

P Regular monitoring of appropriate biochemical indices is also indicated (eg metabolic indicators for drugs particularly associated with metabolic dysfunction), see Table 2.

the original antipsychotic should be commenced. A cautious taper is particularly recommended for a switch from a drug with strong anticholinergic properties, such as olanzapine, in order to avoid cholinergic withdrawal, or the appearance of ADRs which might wrongly be attributed to the aripiprazole.5 The use of SGAs in acute hypomania and mania is now well established, with aripiprazole, olanzapine, risperidone and quetiapine all being licensed in the UK for this indication.3,6-8 Aripiprazole and olanzapine are also licensed in the UK for prophylactic (maintenance) treatment of bipolar disorder. Although ample evidence exists for the use of aripiprazole in bipolar disorder, all the existing guidelines – which were published before the drug was licensed for bipolar disorder in the UK – do not include it. The exception to this is the recent UK consensus statement.4 The March 2009

Bipolar disorder Table 1. Comparison of adverse metabolic changes occurring with second generation antipsychotics1 Medication

Weight gain

Elevated glucose levels

Elevated lipid levels

























0 = no risk or rarely causes adverse effects at therapeutic dose; +, mild or occasionally causes adverse effects at therapeutic doses; ++, sometimes causes adverse effects at therapeutic doses; +++, frequently causes adverse effects at therapeutic doses

ninth edition of the Maudsley prescribing guidelines9 states that aripiprazole may be considered as first-line treatment for mania. Aripiprazole has a different mode of action to other SGAs, being a partial agonist at dopamine D2 and 5-HT1A receptors, and a different ADR profile to other SGAs (see Table 1). The most recent UK guidelines are the Maudsley prescribing guidelines (see Table 3),9 the NICE guidance10 and the British Association of Psycho足pharmacology (BAP) guidelines for treatment of bipolar disorder,11 which have been followed up by a consensus summary regarding maintenance treatment.12 The BAP guidelines are being updated currently. Clear protocols for delivering and monitoring pharmacological and psychosocial therapies should be put in place by local primary and secondary care organisations. These must include, where, appropriate, integrated shared care guidelines with specific, individualised protocols regarding agreements between clinicians on responsibilities for assessment, management and monitoring.10 This guidance has important implications for reduc-

ing the impact of serious ADRs, such as lithium toxicity, renal impairment, weight gain (especially with lithium, olanzapine and valproate), and metabolic disturbances (for example with olanzapine). Table 2 shows the suggested frequency of monitoring of metabolic parameters recommended by the ADA/APA.1

The place of aripiprazole in clinical practice The efficacy and safety profile of aripiprazole in acute mania as monotherapy13 or as an adjunct,14 as adjunctive treatment in mixed states,14 or as monotherapy in maintenance treatment15 has been established through multiple clinical trials. Aripiprazole, unlike some other agents used in acute and maintenance treatment of bipolar disorder, has a relatively low propensity for weight gain and metabolic disturbance. No prolactin elevation or QTc prolongation was observed above placebo level.13 Considering that treatment is usually long-term and compliance is crucial16 a good tolerability profile should definitely be among the information considered when making a prescribing

Table 2. Recommendations for physical monitoring of patients on atypical antipsychotics1 Baseline

4 weeks

8 weeks

12 weeks

3 monthly






Personal/family history




Waist circumference


Blood pressure




Fasting plasma glucose




Fasting plasma lipids



March 2009

5 yearly



Bipolar disorder choice by clinicians, service users and carers. The main ADRs reported with the use of aripiprazole in bipolar disorder have been akathisia, nausea and vomiting.13 Aripiprazole has no significant pharmacokinetic interactions with mood stabilisers, apart from carbamazepine (which interacts with most antipsychotics, the exception being olanzapine), and can therefore be used with lithium, valproate and lamotrigine.

Special prescribing considerations

bly being planned, and continued until term. Lithium is contraindicated in pregnancy, as it may increase the risk of various congenital anomalies, eg fetal heart defects, and may also induce thyroid abnormalities in both the mother and the baby. During pregnancy and lactation, SGAs are generally thought to be a safer option than other mood stabilisers, with the exception of clozapine (which may cause teratogenicity) and olanzapine (which may cause extrapyramidal side-effects in breast-fed infants).17

Female patients Carbamazepine may interfere with the metabolism of some drugs such as the oral contraceptive pill (OCP), and women of childbearing age should be advised to use alternative forms of contraception.

First episode patients These patients may be particularly sensitive to ADRs, and so may require lower doses than those with a more established illness. As bipolar disorder is a lifetime illness generally requiring long-term treatment, the ADR profile Pregnancy and lactation of the initial regimen chosen should be carefully considCarbamazepine and sodium (and semisodium) val- ered for each individual patient, ideally in a collaborative proate are also associated with increased incidence of decision with them and their significant others. neural tube defects, and should be avoided if possible before and during pregnancy. Elderly patients If this is not possible, high dose (5mg) folic acid should In general, these patients should be started on lower be given prophylactically, with the pregnancy prefera- doses, tapered up gradually in smaller increments. In Table 3. Summary of general prescribing guidelines in bipolar affective disorder9 Disorder


Acute mania

P Withdraw antidepressants P If patient is taking a mood stabiliser, check compliance and levels; increase dose if necessary. Consider

adding an antipsychotic; choice should be determined by individual patient profile including ethnicity, ADR profile and pre-existing ADR risk factors P If patient is not on mood stabiliser, commence mood stabiliser (valproate or lithium) or an SGA with mood stabiliser licence P If inadequate response, combine antipsychotic and valproate/lithium P Consider short-term as required benzodiazepines for all patients (lorazepam/clonazepam) Maintenance

P Monitor serum levels. Lithium, valproate, aripiprazole and olanzapine all shown to be effective P Use antidepressants (SSRIs preferred) only in acute depressive episodes in combination with mood stabiliser. P For recurrent depressive episodes, consider lamotrigine or quetiapine with CBT or an SSRI as required

Bipolar depression

P NICE recommend SSRI with mood stabiliser OR quetiapine monotherapy (if not already on an antipsychotic) P If ineffective, add mood stabiliser to quetiapine/olanzapine or lamotrigine, or switch antidepressant to

mirtazapine or venlafaxine. Rapid cycling

P Withdraw antidepressants P Evaluate psychosocial and physical factors: substance misuse, stress, thyroid function, and check

therapeutic serum levels where relevant P Adjust mood stabiliser if necessary; if ineffective, consider either combining mood stabilisers or adding one of the

following: aripiprazole, clozapine (not licensed), lamotrigine, levetiracetam, nimodipine, olanzapine, quetiapine, risperidone, topiramate, thyroxine (no comparative efficacy data for above – depends on patient choice).

March 2009

Bipolar disorder Figure 1. Suggested algorithm for prescribing in acute mania withdraw antidepressants

on mood stabiliser?


check plasma levels and compliance and adjust dose accordingly


continue and monitor


initiate mood stabiliser (ie lithium, valproate, aripiprazole or olanzapine)




consider adding an SGA licensed for acute mania


continue and monitor

NO combination valproate/lithium/ antipsychotic; adjust doses, consider short-term benzodiazepine (lorazepam/clonazepam)


maintenance therapy, doses may be lower than those needed for younger patients. Patients with physical illness There may be interaction with concomitant medications. In patients with mild to moderate hepatic impairment or renal impairment, no dosage adjustment is needed with aripiprazole. When prescribing other SGAs, lower starting doses will be required and, as in elderly patients, increased with caution. Prescribing any SGA for patients with severe liver disease will need very careful management. Information on relevant drug interactions can be found in the Maudsley prescribing guidelines.9 Alcohol is not specifically mentioned, but it should be avoided or used sparingly in conjunction with all CNS medications. P Ruth I Ohlsen is a research nurse and Katherine J Aitchison is senior lecturer in adult psychiatry at the Institute of Psychiatry at King’s College London References

1. American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 2004;27:596-601. 2. Sullivan G, Bienroth M, Jones M, et al. Practical prescribing with

March 2009

action step

decision step

aripiprazole in schizophrenia: consensus recommendations of a UK multidisciplinary panel. Curr Med Res Opin 2007;23:1733-44. 3. Abilify (aripiprazole). SPC. Electronic Medicines Compendium; 2008. 4. Aitchison KJ, Bienroth M, Cookson J, et al. A UK consensus on the administration of aripiprazole for the treatment of bipolar mania. Under review. 5. Lieberman J. Cholinergic rebound in neuroleptic withdrawal syndromes. Psychosomatics 1981;22:253-4. 6. Zyprexa (olanzapine). SPC. Electronic Medicines Compendium; 2008. 7. Seroquel (quetiapine). SPC. Electronic Medicines Compendium; 2008. 8. Risperdal (risperidone). SPC. Electronic Medicines Compendium; 2007. 9. Taylor D, Paton C, Kerwin R. The Maudsley prescribing guidelines. 9th edition. London: Informa Healthcare; 2007. 10. NICE. Bipolar disorder: the management of bipolar disorder in adults, children and adolescents, in primary and secondary care. London: NICE; 2006. 11. Goodwin GM. Evidence-based guidelines for treating bipolar, revised second edition. Recommendations from the British Association for Psychopharmacology. J Psychopharmacol. In press 2009. 12. Young AH, Cookson J, Elliott B, et al. Consensus summary: managing the aftermath of mania – Newcastle 2 September 2005: consensus meeting statement. J Psychopharmacol 2005;20(2 Suppl): 2006. 13. Keck PE Jr, Marcus R, Tourkodimitris S, et al. A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania. Am J Psychiatry 2003;160:1651-8. 14. Vieta E, T’joen C, McQuade RD, 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;Apr 1 (Epub ahead of print). 15. Keck PE Jr, Calabrese JR, McIntyre RS, et al. Aripiprazole monotherapy for maintenance therapy in bipolar I disorder: a 100 week double-blind study vs placebo. J Clin Psychiatry 2007;68:1480-91. 16. Angst F, Stassen HH, Clayton PJ, et al. Mortality of patients with mood disorders: follow-up over 34–38 years. J Affect Disord 2002;68:167-81. 17. Gentile S. Infant safety with antipsychotic therapy in breast-feeding: a systematic review. J Clin Psychiatry 2008;e1-e8 (Epub ahead of print).

Bipolar disorder

Patient choice and physical health in bipolar disorder Helen Millar discusses the burden of physical morbidity in bipolar disorder and the importance of involving patients in management decisions There is emerging evidence that people across the spectrum of severe mental illness suffer higher levels of physical morbidity and mortality than the general population.1 People with a diagnosis of schizophrenia have a reduction in life expectancy of 10 years on average, with 60 per cent of premature deaths not directly related to suicide.2,3 Now there is growing evidence to suggest that this excess burden of physical comorbidity extends to those with a diagnosis of bipolar disorder.4

Sources of medical risk Specific medical disorders that appear to be more common in bipolar disorder than the general population include migraine, asthma, Cushing’s syndrome and CNS pathology such as sub­cortical infarcts or multiple sclerosis.4 In addition there appears to be an increased vulnerability to the modifiable risk factors for cardiovascular disease, namely obesity, smoking, hyper­ tension, dyslipidaemia and type-2 diabetes.3,5-7 Pharmacological agents for bipolar disorder can contribute to medical problems such as obesity, diabetes mellitus, hypothyroidism, thyroid disease, polycystic ovarian disease, renal disease and skin rash.4 Following the introduction of new guidance for the use of atypical anti­psychotic medication for bipolar disorder it is essential that clinicians are aware of the potential adverse effects of the various treatment strategies. These pharmacological interventions, although an advancement in terms of the management of bipolar disorder itself, can exacerbate already existing physical health problems and lead to the development of further problems. In particular, with evidence for potential weight gain caused by some atypical

antipsych­otics and other mood stabilisers,8-10 they can further increase the risk of cardiovascular ­ problems and metabolic disorders such as type-2 diabetes. With this in mind, the recent NICE guideline for bipolar disorder highlighted the excess physical comorbidities in this population and the requirement for comprehensive monitoring of physical parameters.11

Sources of risk of physical morbidity There are other sources of risk which appear to be common across the severe mental illness spectrum. While the pathogenesis of excess morbidity in bipolar disorder remains ill defined, behavioural and socio­ demographic factors have also been implicated. Lifestyle choices including reduced exercise and a more sedentary lifestyle can be due to the symptoms of the mental illness with poor motivation and episodes of mood dysregulation reducing interest in self care and wellbeing. Dietary intake can vary in accordance with cycles of illness with diets more likely to be low in fibre and high in saturated fats. Smoking and abuse of alcohol and illicit drugs can be problematic in this patient group, and will exacerbate any ongoing physical health problems. Other causes of increased cardiometabolic risk include non-disease-related factors such as reduced access to proper health screening services and socio­ economic deprivation.3

Patient choices regarding treatment Bipolar disorder presents as a complex illness to treat with a 90 per cent likelihood of recurrence once an individual has suffered a manic episode. A total of 10–15 per cent of cases present as rapid cyclers with approximately three episodes per year with partial remission in between. Acute depressive episodes are common and may require the addition of antidepressant medications in addition to regular long-term mood stabilisers and March 2009

Bipolar disorder antipsychotics. As a result polypharmacy may be more common than with other disorders, in order to control symptoms and stabilise the condition. Preparations including mood stabilisers, antidepressants and second generation anti­psychotics are an integral part of treatment, with typical antipsychotics only utilised in the management of short-term acute disturbances.11 These treatment options should be carefully communicated to patients in order that they can make informed choices regarding the medications available. From the clinician’s perspective the choice of medication depends on numerous factors, including the patient’s response to previous treatments and the known risk for relapse of manic versus depressive episodes. Physical factors are important in terms of medical history, particularly renal disease, obesity and diabetes. The consensus from the American Diabetes Association (ADA) and the American Psychiatric Association (APA) conference in 2004 reported that antipsychotics can be split into three tiers of risk. Olanzapine and clozapine are associated with the greatest weight gain, the highest number of new-onset diabetes cases and the highest percentage of dyslipidaemias. Risperidone and quetiapine sit at the mid tier of risk and aripiprazole and ziprasidone have a very low potential for weight gain, diabetes or dyslipidaemia.8 In addition to the relative risk for cardiovascular and metabolic complications, patient preference must also be taken into account given the likelihood of reduced adherence to a drug that is poorly tolerated, leading to a worse outcome in the long term. Table 1. Antipsychotic-induced weight gain12 Drug

Risk/extent of weight gain

Clozapine Olanzapine




Chlorpromazine Quetiapine Risperidone


Amisulpride Aripiprazole Haloperidol Trifluoperazine Ziprasidone


March 2009

The Maudsley guidelines outline the relative risk for weight gain with various atypical and typical anti­ psychotics and advise on the treatments for druginduced weight gain and switching strategies to the lower risk agents (see Table 1).12 The choice of drug being prescribed depends on the stage of illness and the symptoms demonstrated and may require trials of several combinations before achieving the optimum treatment. More research is need in this area to clarify the role of these types of drugs in metabolic syndrome in bipolar disorder. The long-term management of bipolar disorder requires careful consideration given the risk of relapse and suicide in this population as well as the increased propensity for metabolic syndrome. Whatever the combination agreed on, the reasons for the choice should be fully discussed with the patient in order that they are clear of the potential benefits and also the risks in terms of relapse prevention and adverse effects. The discussion, decisions and agreements should be documented. The rationale for the commencement and discontinuation of medication should also be clearly outlined in the medical records. Consideration should also be given to other non-pharmacological therapies including cognitive behavioural therapy. Psychological therapy should include education, coping strategies enhancement and relapse prevention work. Focused family intervention may be appropriate to improve family relations, communication and understanding of triggers and relapse prevention.

Metabolic and cardiovascular risk management Studies looking at the prevalence of metabolic syndrome in the bipolar patient population demonstrate high levels compared with the general population. Approximately one third of this patient group appear to be within the category of metabolic syndrome, which is a similar proportion to those with schizophrenia. The presence of metabolic disturbance is a significant risk factor for cardio­ vascular disease and the development of diabetes.6,7,13 Certain atypical antipsychotics have demonstrated an increased propensity to cause weight gain and hence the associated metabolic and cardiovascular longer term complications. Related problems include hypertension, dylipidaemias and glucose intolerance.4,8-10

Bipolar disorder The increased risk of comorbid physical health problems and increased mortality points to the need for early detection, monitoring and appropriate intervention with physical health checks. There has been increased momentum to develop guidelines for patients with bipolar disorder to ensure monitoring and intervention and prevent long-term ­physical health complications. NICE has recommended that people with bipolar disorder should have a health check annually, normally in primary care. A schedule for physical monitoring is included in the bipolar disorder guideline, and incorporates not only the level of mood stabiliser prescribed but a battery of tests including lipid levels, plasma glucose, weight, smoking status and alcohol intake along with blood pressure. These checks can be conducted more regularly if required, for example in the case of thyroid function. It is recommended that physical checks are carried out as soon as practicable after initial presentation. Agreement must be made between mental health and primary care services as to who should be responsible for completing tests, keeping in mind patient preference whenever possible.11 If weight gain is an issue, medication should be reviewed with consideration of dietary advice and exercise, and weight management programmes incorporated into the treatment plan. In order to review medication it is important that there is an understanding by the clinician involved of the potential adverse effects associated with the atypical class of anti­psychotics in order to switch to the lower risk agent where possible. Ultimately the primary concern is to treat symptoms but also to balance efficacy with tolerability issues. Drug treatments to promote weight loss are not recommended. An agreement between primary and secondary care is required in order to follow up abnormal test results and provide appropriate treatment. Hopefully this more holistic approach to the care of people with bipolar disorder will address not only the management of the mental illness but also improve physical wellbeing and therefore overall quality of life.

Conclusion With increasing evidence of higher comorbidity and mortality in those with a diagnosis of bipolar disorder it is

essential that clinicians are aware of the potential sources of risk for cardiovascular and metabolic problems. Although medication remains the cornerstone of bipolar disorder management, utilisation of adjunctive psychosocial treatments and acknowledgement of the model of chronic disease management is crucial. As clinicians we have a duty to improve our knowledge base in order to inform and appropriately communicate both the benefits and risks of the treatment options to patients. It is only by doing so that we can then start to improve both the mental and physical wellbeing of this population by helping them make informed choices regarding treatment strategies. Hence proper health screening needs to be recognised as an integral part of the management of bipolar disorder. Assertive treatment programmes are required to provide equal access to physical health checks and healthy lifestyle advice and interventions in order to reduce morbidity and mortality and improve recovery outcomes. P Dr Helen Millar is consultant psychiatrist at the Carseview Centre in Dundee


1. Newcomer JW. Metabolic syndrome and mental illness. Am J Manag Centre 2007; 13 (7 Suppl): S170-7. 2. Brown S. Excess mortality of schizophrenia. A meta-analysis. Br J Psychiatry 1997;171:502-8. 3. Krishnan KRR. Psychiatric and medical comorbidities of bipolar disorder. Psychosomatic Medicine 2005;67:1-8. 4. Lambert TJ, Velakoulis D, Pantelis C, et al. Medical comorbidity in schizophrenia. Medical J Aust 2003; 178(4 suppl):S67-S70. 5. Newcomer JW. Medical risk in patients with bipolar disorder and schizophrenia. J Clin Psychiatry 2006;67(Suppl 9):25-30. 6. Birkenaes AB, Opjordsmoen S, Brunborg C, et al. The level of cardiovascular risk factors in bipolar disorder equals that of schizophrenia: a comparative study. J Clin Psychiatry 2007; 68:917-23. 7. van Winkel R, De Hert M, Van Eyck D, et al. Prevalence of diabetes and the metabolic syndrome in a sample of patients with bipolar disorder: Bipolar Disord 2008;10:342-8. 8. Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weightgain: a comprehensive research synthesis. Am J Psych 1999;156: 1686-96. 9. Nemeroff CB. Dosing the antipsychotic medication olanzapine. J Clin Psychiatry 1997;58(Suppl 10):45-9 . 10. American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 2004;65:267-72. 11. NICE. Bipolar disorder: the management of bipolar disorder in adults, children and adolescents, in primary and secondary care. London: NICE; 2006. 12. Taylor D, Paton C, Kerwin R. The Maudsley Prescribing Guidelines. 9th ed. London: Informa Healthcare; 2007. 13. D’Mello DA. Prevalence and consequences of metabolic syndrome in bipolar disorder. Psychiatry Times 2007;24(1).

March 2009

Bipolar disorder

Switching medications for bipolar disorder treatment David Yeomans explains the principles of when and how to change drugs for bipolar disorder, and presents a case study of a switch to aripiprazole People with bipolar disorder may not respond to medication, or may not tolerate it. Switching medications can be a way to achieve remission and recovery, and minimise side-effects. Switching is sometimes an arduous process, but can be worth the effort since there is good evidence that medication is effective for acute mania and hypomania, acute and chronic depression and mood stabilisation.1 You must be reasonably confident of the diagnosis to switch treatment. Failure to respond to previous treatment for bipolar disorder could be a result of incorrect diagnosis. Patient–doctor engagement is the key to success in finding a good treatment plan. Medication can be prescribed in a sterile, impersonal way, but goes down more easily if doctor and patient feel positive about each other. Problems that occur along the way are easier to overcome if there is a good relationship at the start. Each person is different. Age, sex, health history and co-morbid conditions may affect treatment selection. Personal views are important. Some people with bipolar I disorder will take medication because they never want to experience such an illness again. Others will be more relaxed about the possibility of recurrence. Some will not acknowledge that they have ever been ill and see little reason to take medication at all. The clinician must use his or her skill to determine how each individual is treated. Some doctors are more ready to diagnose bipolar disorder than others. Some are more ready to prescribe medication combinations. Guidance on treatment can be found in NICE guideline 381 and the Maudsley prescribing guidelines.2 A fuller account of NICE recomMarch 2009

Rationale for switching

P Patient choice: Some people want to change medication and doctors should offer their knowledge and experience as appropriate to explore the issues and advise the patient and their family.

P To improve effectiveness: Ineffective treatment is not acceptable, though changing medication may still be a gamble since new side-effects can arise.

P Concordance: Poor treatment concordance is probably an issue in almost all patients. Switching medications may facilitate concordance by improving effectiveness or reducing side-effects.

P To reduce side-effects: Bipolar treatment is usually long term and side-effects should be minimised. For example, medication-induced weight gain over a long period can increase the risk of diabetes and heart disease. If diet and exercise do not work then switching may help.

P Reconsideration of diagnosis towards bipolar disorder: Diagnoses overlap each other and change over time. Sometimes a change of diagnosis from schizophrenia or personality disorder can lead to a switch of treatment that improves outcomes.

mendations in bipolar disorder is given in Kathy Aitchison’s article in this publication. Second opinions from colleagues can be helpful. In another part of this guide, Helen Millar outlines considerations about physical health and side-effects of medication. It is important to set these out for patients to help them make an informed choice about medication switches.

Treatment approaches Various treatments are used in bipolar disorder: lithium, valproate, antipsychotics, benzodiazepines and anti­

Bipolar disorder depressants. Many of these medications have sideeffects and interactions with other medications. Care needs to be taken when switching to take these effects into account. These drugs have individual pharmacological properties, so the advice given here is a general guide to the principles of switching medication. The approach will need to be adapted to individual circumstances.

How to switch It is important to check for known allergies, and take a history of previous medication changes. Be wary of continuing an extended series of switches that have produced no benefit. You may even consider stopping medication rather than switching if you have doubts about diagnosis or treatment concordance. Clear agreement should be reached about what the expected outcomes of the switch should be. Rapid discontinuation of existing medication is generally not recommended because it can cause unpleasant discontinuation effects. When possible avoid combined doses of medications during a switch that are higher than BNF maxima. This is most difficult at the beginning of a switch and in acute settings. In general switches should be slow, adding in smaller doses of the new medication while reducing the old med-

ication at a rate that minimises the risk of withdrawal effects. The new medication dose can be escalated slowly where appropriate, lessening initiation effects. Be careful if existing medications interact. For example if carbamazepine is co-prescribed with aripiprazole, the dose of aripiprazole may need to be increased since carbamazepine induces the enzymes that metabolise aripiprazole. Patients taking antidepressants and antipsychotics can usually make a cross-tapered switch over three to six weeks (Figure 1). Mood stabiliser switches may take longer. It is worthwhile agreeing a ‘fall-back’ treatment plan in case the switch fails. This could mean reverting to the previous medication.

Preparing the patient It is sensible to discuss withdrawal effects and initiation effects – forewarned is forearmed. Give written information and include a timetable of the switch process for the patient to use as a guide. It is useful to offer a telephone contact point so the patient can ring and check out any issues that arise.

Preparing the clinical team

It can be helpful to involve another member of the team to work alongside you and the patient, in order to share any support New medication activities during the switch period.


Old medication

18 16

Close monitoring of a switch is itself therapeutic and helps instil confidence in the process. It also facilitates detection of side-effects and relapses. The clinician should consider making more frequent visits or clinic appointments.


14 12 10 8 6 4 2 0 5 k W ee

4 k W ee

3 k W ee

2 k W ee

W ee



Contingency plan

Figure 1. Cross-tapered switch



It is a good idea to have a plan to cover contingencies such as initiation side-effects, withdrawal symptoms, relapse, or loss of confidence in the switch process. March 2009

Bipolar disorder Case study A 47-year-old, single, diabetic woman with bipolar disorder for many years and a history of hospital treatment under the Mental Health Act was treated with risperidone 4mg. Although mentally well, she suffered from breast enlargement, nipple discharge, amenorrhoea and elevated prolactin at 2,013miU/l. The risperidone was the likely cause of most of her troubling symptoms. This was switched to aripiprazole over three weeks by reducing risperidone by 1mg/week while introducing aripiprazole at 10mg. Aripiprazole was chosen because, in contrast to most antipsychotics, it has a low potential for both endocrine and metabolic side-effects. She was well for three months, then relapsed and went to hospital where aripiprazole was increased to 20mg and she quickly remitted. Galactorrhoea and breast enlargement subsided fully. Prolactin returned to normal at 99miU/l. She recovered fully within three months. Amenorrhoea persisted due to the menopause. Key learning points

P Hyperprolactinaemia is common with antipsychotics.3 P Medication-induced symptomatic hyperprolactinaemia can be treated by switching to aripiprazole which has a low potential to raise prolactin.4

P Aripiprazole also has a low potential to cause weight gain and impair glucose metabolism.5 P Relapses may occur during, or following a switch. Patients need to know this. There is no need to switch again if the original plan can be supported and maintained.

P In this case the goal of recovery with reduction of side-effects was achieved. The patient has since been discharged to the care of her GP.

Failed switches? When to persist, when to move on When is a switch a failure? Is it at the first sign of difficulties or after a gruelling period of medication-related problems? That depends on the patient and the clinician. If both agree the switch has caused irretrievable problems, then the process should be abandoned. However if the patient is still engaged in the struggle to improve then the switch can continue. Sometimes this may involve a period of more intense care in hospital. Alternatively the switch can be drawn out over several months.

Switching again Patients may wish to try again with another treatment approach. A review of the last switch can give good feedback and support a further change of treatment, if the therapeutic relationship is still strong. Sometimes patients decline further switches and this should be respected. If non-medication approaches have not already been considered, they should be. March 2009

P Dr David Yeomans is consultant psychiatrist at Leeds Partnerships Foundation NHS Trust and honorary senior lecturer at the University of Leeds. He is a trustee of Leeds Mind and his research interests include the physical health of people with severe mental illness, clinical outcomes and exam technique.


1. NICE. Bipolar disorder: the management of bipolar disorder in adults, children and adolescents, in primary and secondary care. London: NICE; 2006. 2. Taylor D, Paton C, Kerwin R. The Maudsley Prescribing Guidelines. 9th ed. London: Informa Healthcare; 2007. 3. Bushe C, Yeomans D, Floyd T, et al. Categorical prevalence and severity of hyperprolactinaemia in two UK cohorts of patients with severe mental illness during treatment with antipsychotics. J Psychopharmacol 2008;22;56-62. 4. Sachs G, Sanchez R, Marcus R, et al. Aripiprazole in the treatment of acute manic or mixed episodes in patients with bipolar I disorder: a three-week placebo-controlled study. J Psychopharmacol 2006;20:536-46. 5. De Hert M, Hanssens L, van Winkel R, et al. A case series: evaluation of the metabolic safety of aripiprazole. Schizophrenia Bull 2007;33:823-30.