Practical Management of Bipolar Disorder

Practical Management of Bipolar Disorder

Practical Management of Bipolar Disorder Edited by Allan H. Young Department of Psychiatry, University of British Columbia, Vancouver, Canada

I. Nicol Ferrier Institute of Neuroscience, University of Newcastle, Newcastle upon Tyne, UK

Erin E. Michalak Department of Psychiatry, University of British Columbia, Vancouver, Canada

c a mb rid g e u n iver si t y pres s Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore, São Paulo, Delhi, Dubai, Tokyo Cambridge University Press The Edinburgh Building, Cambridge CB2 8RU, UK Published in the United States of America by Cambridge University Press, New York www.cambridge.org Information on this title: www.cambridge.org/9780521734899 © Cambridge University Press 2010 This publication is in copyright. Subject to statutory exception and to the provisions of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Cambridge University Press. First published 2010 Printed in the United Kingdom at the University Press, Cambridge A catalogue record for this publication is available from the British Library ISBN 978-0-521-73489-9 Paperback Cambridge University Press has no responsibility for the persistence or accuracy of URLs for external or third-party internet websites referred to in this publication, and does not guarantee that any content on such websites is, or will remain, accurate or appropriate. Every effort has been made in preparing this book to provide accurate and up-to-date information which is in accord with accepted standards and practice at the time of publication. Although case histories are drawn from actual cases, every effort has been made to disguise the identities of the individuals involved. Nevertheless, the authors, editors and publishers can make no warranties that the information contained herein is totally free from error, not least because clinical standards are constantly changing through research and regulation. The authors, editors and publishers therefore disclaim all liability for direct or consequential damages resulting from the use of material contained in this book. Readers are strongly advised to pay careful attention to information provided by the manufacturer of any drugs or equipment that they plan to use.

Contents List of contributors

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1. Reflections and insights from the ‘lived’ experience 1 Victoria Maxwell

13. Bipolar disorder co-morbid with addictions 129 Jose M. Goikolea and Eduard Vieta

2. Overview of bipolar disorder 9 Allan H. Young, I. Nicol Ferrier and Erin E. Michalak

14. Practical management of cyclothymia 139 Giulio Perugi and Dina Popovic 15. Circadian and sleep/wake considerations in the practical management of bipolar disorder 152 Greg Murray

3. The treatment of mania 10 Heinz Grunze 4. Pharmacological treatment of bipolar depression 24 Allan H. Young and Charles B. Nemeroff

16. A clinician’s guide to psychosocial functioning and quality of life in bipolar disorder 163 Erin E. Michalak and Greg Murray

5. Practical treatment guidelines for management of bipolar disorder 33 Lakshmi N. Yatham

17. Service delivery of integrated care for bipolar disorder 175 Richard Morriss

6. Psychosocial interventions in bipolar disorder: theories, mechanisms and key clinical trials 44 Sagar V. Parikh and Vytas Velyvis 7. Physical treatments in bipolar disorder Marisa Le Masurier, Lucie L. Herrmann, Louisa K. Coulson and Klaus P. Ebmeier

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8. Treating bipolar disorder in the early stages of illness 73 E. Jane Garland and Anne Duffy 9. Special populations: the elderly 84 Alan J. Thomas 10. Special populations: women and reproductive issues 93 Karine A.N. Macritchie and Carol Henshaw 11. Physical health issues 106 Chennattucherry John Joseph and Yee Ming Mok 12. Anxiety associated with bipolar disorder: clinical and pathophysiological significance 120 Pratap R. Chokka and Vikram K. Yeragani

18. Training and assessment issues in bipolar disorder: a clinical perspective 184 Sagar V. Parikh and Erin E. Michalak 19. Practical guide to brain imaging in bipolar disorder 194 I. Nicol Ferrier and Adrian J. Lloyd 20. From neuroscience to clinical practice 199 Annie J. Kuan, Vivienne A. Curtis and Allan H. Young

Index

210

The colour plates can be found between pages 184 and 185.

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Contributors

Pratap R. Chokka Department of Psychiatry, University of Alberta and Grey Nuns Hospital, Edmonton, Alberta, Canada Louisa K. Coulson Department of Psychiatry, University of Oxford, Oxford, UK Vivienne A. Curtis Maudsley Hospital and Institute of Psychiatry, London, UK Anne Duffy Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada

Chennattucherry John Joseph Department of Liaison Psychiatry, Royal Victoria Infirmary, Newcastle upon Tyne, UK Annie J. Kuan Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada Adrian J. Lloyd Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK

Klaus P. Ebmeier Department of Psychiatry, University of Oxford, Oxford, UK

Karine A.N. Macritchie Institute of Mental Health, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canda

I. Nicol Ferrier Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK

Marisa Le Masurier Department of Psychiatry, University of Oxford, Oxford, UK

E. Jane Garland University of British Columbia and British Columbia’s Children’s Hospital,Vancouver, British Columbia, Canada

Victoria Maxwell Crazy for Life Co., Sechelt, Canada

Jose M. Goikolea Bipolar Disorders Program, Institute of Clinical Neuroscience, University of Barcelona, Barcelona, Spain Heinz Grunze Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK Carol Henshaw Staffordshire University and Liverpool Women’s NHS Foundation Trust, Liverpool, UK

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Lucie L. Herrmann Department of Psychiatry, University of Oxford, Oxford, UK

Erin E. Michalak Mood Disorders Centre, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada Yee Ming Mok Institute of Mental Health, Woodbridge Hospital, Singapore Richard Morriss University of Nottingham, Nottingham, UK Greg Murray Swinburne University of Technology, Melbourne, Australia

List of contributors

Charles B. Nemeroff Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, USA Sagar V. Parikh University Health Network, Toronto Western Hospital, Toronto, Ontario, Canada Giulio Perugi University of Pisa, Pisa, Italy Dina Popovic Institute of Behavioural Science ‘G De Lisio’, Pisa, Italy Alan J. Thomas Wolfson Research Centre Institute for Ageing and Health, Newcastle University Campus for Ageing and Vitality, Newcastle upon Tyne, UK

Vytas Velyvis Ontario Shores Centre for Mental Health Sciences, Ontario, Canada Eduard Vieta Bipolar Disorders Program, Institute of Clinical Neuroscience, University of Barcelona, Barcelona, Spain Lakshmi N. Yatham Mood Disorders Centre, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada Vikram K. Yeragani Wayne State University School of Medicine, Detroit, USA Allan H. Young Institute of Mental Health, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada

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Part 1 Chapter

21

Reflections and insights from the ‘lived’ experience Victoria Maxwell

Introduction: practical for both clinician and consumer Bipolar disorder (BD) destabilises more than just a person’s mood, thinking and physiology. It subverts one’s identity, life and dreams. It is a disease that ferociously and expertly destroys lives and the sense of meaning, not just of the individual who has the illness but those loved ones around that person. I know. After what was thought to be a brief reactive psychosis (by the way: nothing is really brief when it comes to psychosis), I was eventually diagnosed with rapid-cycling, mixed state BD with psychotic features, mild temporal lobe epilepsy and generalised anxiety disorder. The regrettable (and sadly common) fact is that it took many more psychotic, manic and depressive episodes over a four-year period before I would accept I had BD. And it took an additional five years to regain some semblance of self-esteem and confidence and return to the workforce and independent living. Prior to and during those first four years, my career careened out of control, my significant other left, my money evaporated, my friends were scared off, my car and home were no longer affordable and my idea of myself permanently changed. The assistance I received from the health professionals who worked with me (more accurately who tried to work with me – I wasn’t exactly a willing participant for those first few years) included potentially helpful treatment plans and medication regimes. However, I didn’t care about these plans – I cared about gathering what was left of my life (and my dignity) and envisioning something beyond attending self-help meetings and cognitive behavioural therapy sessions and cashing welfare cheques and living with my parents. Understandably, wellness is defined in various ways by different groups. Decreasing the occurrence of disabling symptoms is not to be dismissed. Those living with BD know the importance of being able to get out of bed and to be free of the relentless fatigue that dogs us during

depression. But to have a reason and a life to get out of bed for is at the heart of wellbeing. It is something that must be taken into consideration when creating treatment plans – it encompasses wholly different elements but is as essential as reducing episodes of psychosis, mania and depression. To be truly practical, the management of BD must go beyond the reduction of symptoms. It is about understanding what we, as your patients, want in specifics. Does your patient want to work full time, have children, go back to school, afford a car, learn to cook, have a circle of friends, quit smoking, live downtown but not on the Eastside? To be valuable to us, your help must be relevant to our daily lives. That is why including the consumer in the planning of treatment and in the process of delivery of those treatments is essential. Shared decision-making is pivotal. It is also why I am grateful and honoured to be contributing to this guide as one voice of the consumer. In order for this guide to be practical, the information and tactics lying within these pages must in the end benefit not only you, but the patients you serve. In this chapter I discuss, from the perspective of someone who lives with BD, what makes a guide like this practical to those of us with the illness, and what recovery means and how it relates to the chapters that follow; I also introduce the concept of ‘personal medicine’ and the critical connection treatment must make with it.

Recovery, personal medicine and treatment: the critical connection Instead of focusing primarily on symptom relief, as the medical model dictates, recovery casts a much wider spotlight on restoration of self-esteem and identity and on attaining meaningful roles in society. (US Department of Health & Human Services, 1999)

As mentioned previously, symptom abatement alone is not synonymous with recovery. A life defined by decreased hospital days or better medication adherence is only part of the formula indicating recovery and one that is unsatisfactory at best. Dr Patricia Deegan, a

Practical Management of Bipolar Disorder, eds. Allan H. Young, I. Nicol Ferrier and Erin E. Michalak. Published by Cambridge University Press. © Cambridge University Press, 2010.

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clinical psychologist and pioneer in the mental illness recovery movement and the study of resilience (who also happens to live with schizophrenia), eloquently states: ‘recovery is about changing our lives, not just our biochemistry’ (Deegan, 2005). Indeed, having a sense of purpose, feeling like a valued part of the community despite experiencing symptoms of BD, is at the core of what it means to be in recovery. Whether we experience intense symptoms or few at all, we as consumers – like all of us really – need to feel our lives have significance, that our lives have meaning, or that at the very least we are creating meaning. All of us, regardless of our state of health, utilise what Dr Deegan terms ‘personal medicine’ (PM), which she defines as the things that give life meaning and ‘make life worth living’ (Deegan, 2004; Deegan, 2005). This idea of personal medicine is integral to recovery and must be taken into account when creating and executing recovery plans for an individual.

Personal medicine defined

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The term coined by Deegan refers to activities or wellness strategies we do, rather than things we ingest. They are not goals we set or feelings we have. They are not over-the-counter mixtures of our own making. They are behaviours that enhance our sense of purpose, raise our self-esteem, engage our deepest values and beliefs and improve our wellbeing. At first glance, PM may seem overly simplistic and self-evident, but these behaviours and the ability to engage and align treatment with them have profound impact on patients’ recovery and their adherence to treatment plans. Crucial to note is the delicate and often underestimated interplay between PM and treatment. In studies carried out by Deegan, discovering, understanding and aligning medical treatment with a patient’s PM can increase medication adherence. She states that ‘medication adherence may be improved when clinicians inquire about patients’ personal medicine and use pharmaceuticals to support, rather than interfere with, these self-assessed health resources’ (Deegan, 2005). As we explore PM further it will also become apparent that this element in a person’s life may be one of the most cost-effective and efficient means of engaging that individual in treatment, as long as this one guideline is followed: medical treatment must align with and complement PM, not the other way around. That is, in order for adherence to improve, treatment and medication must support, not interfere with, PM. Therefore the continued maintenance of PM in a patient’s life must

be the priority. Treatment and medications are to be adjusted to the PM in order to interfere as little as possible with the ability to engage in the individual’s PM. I know this to be true from my own experience. I have seen and continue to see this phenomenon in action.

Categories, subtypes and unique features of PM Personal medicine is not instead of, but in addition to, medication and other forms of treatment. It expands and challenges our idea of traditional medicine, entailing a broader definition of how an illness can be treated. All of us have examples of PM in our lives. For me, these include: window shopping for shoes (note the operative word, ‘window’ – remember I have bipolar disorder); listening to almost any song of Joni Mitchell or Emmylou Harris; running in trails near my home; watching reruns of ‘Friends’; being able to work and perform full time; soaking in our hot tub; spending time with my husband; reading fiction by my favourite authors; and prayer. Personal medicine works simultaneously, on multiple levels, is interdependent and rests on a spectrum. Deegan cites two categories of PM: self-care strategies and activities that give meaning and purpose (Deegan, 2005). Within each of those two classes of PM, I distinguish two further types (Figure 1.1): (1) self-care strategies that soothe the self and decrease the intensity of and occurrence of symptoms; and (2) activities that engage and enhance core ethics and identity.

Dual functionality of a PM measure Within these two groups, the actions can either contain or activate energy (Erin Michalak, personal communication, 2009). Paradoxically, the same behaviour can accomplish both activation and containment. For example, running in trails for me: when hypomanic, running serves to contain and channel my extraneous energy; when experiencing depression, running and the outdoor environment stimulate dormant energy and counteract inertia. Another example that echoes this dual function is spending one-on-one time with my husband: when I am cycling through mild mania, my time with him acts as a grounding agent, calming and directing my frenetic energy; when I am depressed, his presence soothes and stimulates my enervated sense of aliveness.

Interplay between PM and treatment adherence How does this alignment of PM and treatment and medication work to increase treatment adherence?

Chapter 1: The ‘lived’ experience

Works simultaneously, on multiple levels, is interdependent and rests on a spectrum

Self-care strategies to soothe and subdue

Actions that engage & enhance core values and self-image

Figure 1.1 Types of personal medicine.

Most PM is present before the onset of the illness and certainly precedes the diagnosis (Deegan, 2005). In addition, PM is actively pursued despite, or perhaps because of, the illness, in order to create some familiarity. Just as personality traits and interests generally remain constant throughout an individual’s life (Costa & McCrae, 1997; Soldz & Vaillant, 1999), so too those activities considered to be PM remain stable and persistent (Low & Rounds, 2007). We are intrinsically motivated to continue doing these actions because they are highly valued and connected to our core principles. Because there is a pre-existing commitment to engage in the PM, the actions are most often self-initiated. These behaviours that help create meaning in a patient’s life, that help restore esteem, are also at times compromised and limited by treatment and the side effects of medication. And frequently, a patient is encouraged to tolerate these impositions rather than being given the opportunity, no less the power, to explore options to better integrate the suggested recovery plans into existing and personally important PM.

Discussing PM with patients to avoid non-adherence Why must health providers make discussing and identifying current and potential PM with their patients a priority? Part of treatment needs to be working with the patient to identify current PM and discover new or latent PM. As Rapp describes in his strengths approach (Rapp, 1998), it is imperative and more effective to concentrate on what is already working in an individual’s life or what has worked in the past. The congruency between treatment and PM will provide a vehicle to engage the patient proactively and to benchmark

Box 1.1. Personal medicine (PM) primer • All of us practise PM, regardless of wellbeing • PM pre-exists illness and diagnosis • PM is as crucial to recovery as medication and other treatment plans • Harmony between PM and treatment and medication is key to improving adherence and outcomes • Patients do not commonly disclose PM to their clinicians • Clinicians do not often enquire about patients’ PM • If clinicians begin a dialogue with patients about PM, medication adherence is likely to improve, in addition to quality of life • Providers can be of most benefit by helping patients to identify current PM and discover new PM • Ideally this discussion is done before or alongside the prescription of medication or other treatments.

significant barriers to taking medication or accepting certain treatment plans. The most effective management of BD ensures that prescribed treatment and medication supports rather than encumbers individualised life goals, current ‘meaning-making’ activities and already existing valued aspects and coping tools within your patient’s life. This may seem like common sense, but unfortunately, common sense is not always common practice. More accurately even, practitioners often believe they understand this interplay and already align PM with medication and treatment. But I would dare to differ. The subtlety of PM is underestimated, as is the hesitation – and quite frankly fear – that we as patients have in challenging our health-care provider’s mandates. Non-adherence to medication and other treatment elements is a common issue in BD (Lingam & Scott, 2002). Studies indicate that over 60% of patients with BD have some adherence difficulties with medication (Gaudiano et al., 2008). But the real reasons for the resistance are often misunderstood. Exploring a patient’s PM and how that patient personally defines quality of life are keys to removing barriers to treatment cooperation (Box 1.1).

PM and removing barriers to treatment and medication adherence: real-life examples As Deegan asserts, ‘non-adherence with prescribed psychiatric medications was found to occur when pharmaceuticals interfered with personal medicine resulting in a diminished quality of life’ (Deegan,

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2005). I have acutely experienced how the failure to enquire about my PM resulted in my refusal to take medication, even to accept the diagnosis of BD, and resulted in much more time being sick. When I had my first psychotic experience, I was in a meditation group and involved in an intense spiritual practice. My manic psychosis was, in fact, very important to me. Although obviously many aspects were delusional, some also held valuable and cherished spiritual insights for me. But when I landed in the hospital, what I underwent was pathologised, and medication was prescribed so that it never happened again. One well-meaning, but misdirected doctor emphasising the benefits of pharmacology, explained to me: ‘We don’t want you to go down that path again. . .’ What he failed to realise is that the ‘path’ that he saw only from a medical model, I held in a much wider framework. Like many in Deegan’s study, I didn’t discuss my interest in pursuing meditation and my practice further, as I feared, understandably, that it would not meet with the approval of my doctors (Deegan, 2005). In my mind I was being prescribed mood stabilisers, antipsychotics and antidepressants to eradicate the very thing that gave meaning to my life. So I refused to take them. Rather than a discussion taking place about my PM and how the medication and diagnosis undermined it, a power struggle between me, my family and my psychiatrist began. When faced with the choice of either taking pharmaceuticals and denying my spiritual life or refusing medication but embracing my relationship with my spirituality regardless of the symptoms I might have to endure – it was obvious to me which I was going to choose. It wasn’t until further manias, several additional psychoses and more trips to the hospital, where I met a different psychiatrist, that a breakthrough occurred. In my initial meeting with this doctor he asked me to explain what led to my first psychosis, and what the meditation I was engaged in meant to me. In essence, he was exploring my PM in order to understand the vital role it played in my life. This astute doctor worked with me and discussed how to incorporate my desire, and in fact my need, to follow my spiritual path with the goals of medication and his treatment plans. Our time together became a process of shared decision-making (Deegan & Drake, 2006). We agreed that temporarily I would put meditation on the ‘back burner’, and instead I would find a spiritual counsellor to help make sense of what happened to me and put it in a context that would be meaningful. This wise doctor told me that having a spiritual experience (which is how I defined what I went through, at least in part) and a mental illness are not mutually

exclusive. It is not an ‘either/or’ scenario. Most importantly we discussed the fact that if I accepted I had the mental disorders I had been diagnosed with and took the medication prescribed, this in no way had to minimise the impact of what I went through or render it meaningless and merely a result of the illnesses. I see in hindsight that without either of us knowing it, he was ensuring that the treatment and medication goals were in harmony and alignment with one of my most important self-assessed health resources, or my PM. Other examples can be less complex but no less pivotal. As one woman diagnosed with anxiety and BD explained to me: When I am as anxious and depressed as I am, it’s important to be able to enjoy the small things. So when I get drowsy too early to watch my favorite TV show or not be able to get up in the morning and be able to be clear headed to write my to do list . . . I don’t want to take my medication . . . it’s not the kind of life I want (Velma, personal communication, 2008)

The ability to watch a much-loved television programme can be an important ingredient in a patient’s recovery plan – and if it is one of the few activities a person is willing or able to partake in, it is essential that medication and treatment support these endeavours. Although hesitant to ‘complain’ about side effects and ask for the pills to be adjusted, Velma eventually did speak with her doctor to find a better match of medication to her PM. Although I am speaking from my ‘lived’ experience and with anecdotal evidence, I posit that the more that prescribed pharmaceuticals and treatments plans align with an individual’s already established and strongly embraced PM, the more a person will comply. And the more likely a person’s quality of life will improve, even if symptom abatement does not occur fully. And if this discussion happens early on, during the initial stages of intervention with the health-care provider and patient, the better the rapport and the less likely non-adherence will take place.

PM as priority Self-perpetuating reinforcement phenomenon of alignment When clinicians I work with make my PM the benchmark from which to develop my treatment and set the goals of my medication, an interesting process begins to occur. I have also witnessed this sequence of events in others as they work with doctors who make PM the starting point. Deegan & Drake describe it as the

Chapter 1: The ‘lived’ experience

• The more my doctor helps me to align my treatment with my existing PM… • The more valued and respected I feel…

Figure 1.2 Self-perpetuating reinforcement phenomenon of alignment, or Deegan’s ‘cascading effect of personal medicine and psychiatric medication’.

• The better the rapport I have with my doctor; the more I trust him/her... • The more willingly I embrace treatment plans… • The more my wellness improves… • The more my self-esteem improves… • The more I practise my PM… • The more I adhere to treatment… • The more my wellness improves… • The more I adhere to treatment and practise my PM…

‘cascading effect of personal medicine and psychiatric medication’ (Deegan & Drake, 2006). I see it in a more comprehensive light, enlarging the focus to highlight the potent effect the congruency of treatment with PM has on the recovery process. I call it the ‘self-perpetuating reinforcement phenomenon of alignment’. Figure 1.2 outlines what occurred and continues to occur when my psychiatrist takes into account my PM first rather than focusing solely on symptom abatement. This is not to say that the reduction of symptoms is not important, but if it comes at the cost of cherished wellness activities and beliefs, then any decrease in symptoms may not be seen as important from a patient’s perspective. I experience this process to this day, and I see others experience it on their journey to recovery. As with any other course of action, there may be setbacks, but the overall effect is one of growth and improvement.

The interrelatedness of respect, rapport and recovery A myriad studies reveal the same conclusion: rapport of the clinician with the patient is one of the most powerful agents of change when it comes to positive outcomes and recovery (Luborsky et al., 1985; Truax & Carkhuff, 1967). And this is even more salient when it comes to blending treatment with PM. Within this sequence of events, rapport and trust with the clinician prove to be essential components. Without strong therapeutic alliance and attunement, this ‘self-perpetuating reinforcement phenomenon of alignment’ will not easily occur. When we are treated as partners in the process of our recovery, where opportunities are set up for shared decision-making and to discuss our PM, this is when true healing can occur. Even in the acute stages of our illness – mania, depression and psychosis – in which our

ability to contribute and make sound decisions is limited, if we are treated with respect and given an opportunity to contribute in any way, no matter how small, this is never forgotten. This is healing in and of itself. When the opposite occurs, when I am almost literally locked out of discussing my own recovery process, not only does healing not occur, but in fact damage is also done. It is close to impossible to tell how aware a person is when they are actively manic or psychotic and just what will be remembered. But I’d advise you to err on the side of caution. Awareness is a powerful and mysterious element that should not be underestimated. Each time I entered into psychosis and mania, I was acutely conscious of how I was being treated, even if it was impossible for me to express that. I clearly recall – although floridly psychotic and struggling to free myself from the straps that held my wrists in place – the words that spouted from an emergency room worker as I made a run for a nearby washroom: ‘Hey. . .stop the crazy woman!’. I can laugh at it now, but days later in the hospital and months later in my life, those words scalded me to the core when I thought of them. However, I also recollect just the opposite experience when the female police officer and two ambulance attendants caught up with me after I had decided (in another manic psychosis) to take an ecstatic skip through my neighbourhood ‘sans clothes’. I recall the kind way the officer reassured me and offered me a blanket, how the EMS workers gently guided me into the ambulance and sat me down. It was the look in their eyes, the language of their body and face – you can’t fake compassion. I never met the officer or those attendants again; I wish I had (under different circumstances, mind you). I would thank them for giving me hope and respect. Their behaviour registered within me (perhaps my unconsciousness, initially). But that experience stays with me. And for years it was a beacon of encouragement and flame of promise

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that I might indeed recover. That brief encounter with them gave me a palpable and lasting sense that I was something, someone other than my illness; the way they treated me indicated they saw who I was – not what I had become. It is not just what my health-care providers say, or even whether what my clinicians suggest as a treatment works (although this is important); more vital is how they make me feel when I leave their offices. It is exciting to see the emphasis on making the data in each of the following chapters relevant to the lives of individuals like myself who live with the illness – the consumers. Your rapport with your patients is one of those invisible factors that will determine the level of wellness they will reach, and whether or not adherence continues to be an obstacle. I invite you to listen, not just to what your patients are telling you, but also to what they aren’t telling you – and in fact why they don’t.

Summary When clinicians inquire about a patient’s PM, and align treatment and pharmaceutical goals with it, nonadherence is likely to be diminished. This is because important activities and core values of the patient are not disrupted, and the patient’s quality of life remains a priority, not just the reduction of symptoms.

Accurate reflection of bipolar disorder in the chapters that follow

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It is both eerily and excitingly surreal to see my life distilled into precise clinical depictions. Seeing the words ‘anxiety’ and ‘lethality’ bookending the illness I live with is at once both frightening and encouraging. Encouraging? Yes, because I have been fortunate to receive and eventually actively participate in treatment for BD that has allowed me to regain a meaningful life. I missed falling into the crevasse of completed suicide, active addiction and chronic anxiety. This is because, like the researchers and practitioners who are the authors of the words that follow, those of you reading these pages are clinicians who care deeply about helping the people you work with. As I review the various chapters, I can’t help but be stunned at how my personal experience is reflected, and faithfully so, in the wide array of scientific research. Far from feeling like a number in a study, I feel somehow validated and comforted. My ‘lived’ experience is ‘normal’ (for a person with bipolar disorder, that is). It’s good to be normal sometimes. I am not alone in

what I have undergone – repeated hospitalisations, denial of the diagnosis, resistance to take prescribed medication or in the length of time or the challenges I faced – it took over four years for me to accept the illness and another five to live independently and regain employment. Apparently I am a textbook case of BD (much to the chagrin of my ego). In Chapter 8, Drs E. Jane Garland and Anne Duffy cite among other conclusions that ‘at least one-quarter of patients with bipolar disorder experience the onset of their first major mood episode during adolescence. . .which is usually depressive and (have) a positive family history of bipolar disorder.’ With hindsight I recognise that my first major depressive episode, which went undetected and was chalked up to adolescent angst, was around the age of 17. Anxiety, an aspect that Garland explores, was present as early as 8 years old but again went undetected, manifesting itself in a refusal to go to school, social awkwardness and home sickness (which lasted until I was almost 13). The generalised anxiety, however, persisted throughout and into my adult years, co-occurring with my mood disorder. My mother was hospitalised several times before being diagnosed with BD when I was 8 and relapsed into depression several times over the course of my childhood. I had what I kindly call a ‘double-barrelled’ genetic vulnerability: my mother has BD and anxiety; my father was never diagnosed with but dealt with anxiety and depression; and many of my relatives on my father’s side make up a motley crew of individuals with different psychiatric disorders. So goes the luck of the draw. I doubt I will ever wear a pink ribbon and run for breast cancer – my genetics are not stacked in that direction – but I am already hoping I can wear a coloured ribbon and do a 10 k for my wonky brain in the not-sodistant future. Again my profile is unmistakably reflected in other chapters, such as Chapter 6 with a review and comparisons of various psychosocial interventions by Drs Parikh and Velyvis. They describe the study of Lam and colleagues (Lam et al., 2004) in which traits of ‘perfectionism and excessive striving for achievement may confer increased vulnerability to experience mood relapse’. All through high school, in university and as I pursued my acting career, I set high – and frequently unrealistic – goals, fuelling a sense of failure when these targets weren’t met. And perfectionism was learned early from my mother – again feeding

Chapter 1: The ‘lived’ experience

a sense of anxiety, insecurity and helplessness as I unsuccessfully met my self-imposed goals. All of this contributed to feelings of low mood and anxiousness – emotions that eventually developed into painful clinical depression and a nerve-racking anxiety disorder. Although my pursuit of achievement is still strong, it is manageably so. The perfectionism I wrestled with for years thankfully left after a good amount of time in psychotherapy – in large part due to the cognitive therapy. Paradoxically, as my perfectionism faded into the background, my ability to reach my goals successfully increased. In addition, Parikh and Velyvis explain that psychoeducation is loosely based on the age-old adage that ‘knowledge is power’. And as such, patients make better decisions about their illness based on accurate information offered in such interventions. This is evident in my own journey to wellness – once the myths of mental illness and psychiatric medications I held were exposed, the easier it was to accept treatment as it was prescribed. As I gained correct information about how and why doctors believed pharmaceuticals would work – and that indeed BD is as biological as it is environmental and how those elements interact – the less problematic it was for me to admit I had a mental illness (several actually) and that the antidepressant and mood stabiliser I was prescribed were necessary. I recognised that my personal determination to get well would not be enough. In doing so, my adherence to medication and treatment improved. In Chapter 16, Drs Erin Michalak and Greg Murray beautifully articulate what I feel must be foremost in the minds of practitioners when treating BD: that functioning and quality of life are as significant, if not more so, than improvements in symptoms. In addition, I echo the sentiment that there has been a misplaced assumption that symptoms and functioning are highly related.

Conclusion This guide offers concrete tools and data that can result in better and more positive outcomes for those of us living with BD – not necessarily quickly or easily, but over time and with effort and patience. And when we work as partners, this knowledge can be harnessed into power. The alignment of treatment with a patient’s PM also plays an integral role in the effectiveness of the treatment you offer. Ours is a symbiotic relationship. I rely on your expertise, and you rely on my feedback to inform the application of your expertise.

I still face bouts of depression (milder ones mind you, but disruptive all the same) and mini hypomanias, yet I live with a strong sense of recovery and self – a purposeful existence that incorporates meaningful relationships, a rewarding career, a robust identity and goals I actively pursue. This is a result of the tools I use to stay mentally well and manage my illnesses. Key reasons I am willing to be proactive and take charge of my mental health are the relationships my health professionals have established with me and the respect they have of my personal medicine. They work with me as partners, reminding me my insight into my illnesses is more crucial than their and is equally as important and is equally as important as their clinical expertise. This dynamic is what keeps me well. And this I am grateful for – just as I am grateful to contribute a voice to this text.

References Costa, P.T. & McCrae, R.R. (1997). Stability and change in personality assessment: the revised NEO Personality Inventory in the year 2000. Journal of Personality Assessment, 68, 86–94. Deegan, P.E. (2004). Recovery journal: the importance of personal medicine. www.patdeegan.com/blog/ archives/000013.php [accessed 1 March 2009]. Deegan, P.E. (2005). The importance of personal medicine: a qualitative study of resilience in people with psychiatric disabilities. Scandinavian Journal of Public Health Supplement, 66, 29–35. Deegan, P.E. & Drake, R.E. (2006). Shared decision making and medication management in the recovery process. Psychiatric Services (Washington, D.C.), 57, 1636–9. Gaudiano, B.A., Weinstock, L.M., Miller, I.W. (2008). Improving treatment adherence in bipolar disorder: a review of current psychosocial treatment efficacy and recommendations for future treatment development. Behavior Modification, 32, 267–301. Lam, D.H., Wright, K., Smith, N. (2004). Dynsfunctional assumptions in bipolar disorder. Journal of Affective Disorders, 79, 193–9. Lingam R. & Scott, J. (2002). Treatment non-adherence in affective disorders. Acta Psychiatrica Scandinavica, 105, 164–72. Low, K.S. & Rounds, J. (2007). Interest change and continuity from early adolescence to middle adulthood. International Journal of Educational and Vocational Guidance, 7, 23–36. Luborsky L., McLellan A.T., Woody G.E., O’Brien C.P., Auerbach A. (1985). Therapist success and its determinants. Archives of General Psychiatry, 42, 602–11.

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Chapter 1: The ‘lived’ experience

Rapp C.A. (1998). The Strengths Model. New York: Oxford University Press. Soldz, S. & Vaillant, G. (1999). The big five personality traits and the life course: a 45-year longitudinal study. Journal of Research in Personality, 33, 208–32. Truax C.B. & Carkhuff R.R. (1967). Toward Effective Counseling and Psychotherapy. Chicago: Aldine Publishing.

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US Department of Health & Human Services (1999). Mental Health: a Report of the Surgeon General, Chapter 2, Section 10. www.surgeongeneral.gov/library/ mentalhealth/chapter2/sec10.html [accessed 1 March 2009].

Part 1 Chapter

2

Overview of bipolar disorder Allan H. Young, I. Nicol Ferrier and Erin E. Michalak

Bipolar disorder (BD) is a complex mood disorder that is typically characterised by recurring episodes of depression and mania (a distinct period of abnormally elevated, expansive or irritable mood) called BD type I, or depression and hypomania (a less severe form of mania) called BD type II. The past two decades have witnessed a burgeoning of interest in BD. This has been fuelled in part by a wealth of new research evidence but also by an increasing understanding of the significant impact that this severe illness has, not only for sufferers and their loved ones, but also society more broadly. Bipolar disorder is surprisingly common; BD type I and type II subtypes have a lifetime prevalence of between 1 and 2%, and the bipolar spectrum, a category about which much remains unknown, is found in up to an additional 5% (Angst, 2007). The World Health Organization (WHO) has estimated that BD is the sixth leading cause of disability worldwide among young adults (Murray & Lopez, 1997), underlining the idea that BD is a serious public health concern. Advances are being made in the understanding of the aetiopathogenesis of BD, with certain genes being strongly implicated for the first time and other modalities, such as neuroimaging, identifying fruitful leads. Research interest is also being focused upon issues such as physical morbidity and neurocognition. An avalanche of publications has reported new data on treatment modalities, including psychosocial, somatic and pharmacological interventions. The impact of BD on outcomes such as psychosocial functioning and quality of life is being explored. It is within the context of this sometimes overwhelming and confusing proliferation of new knowledge that we frame this book. Our objective is to provide a practical and pragmatic guide to the management of BD for the busy clinician. To this end we have sought contributions from acknowledged experts in BD that provide contemporary evidence-based reviews and insights into areas of prime clinical relevance. We have chosen to begin the book from the perspective of an individual who is

living with BD (Maxwell), underscoring our belief in the importance of maintaining a patient-centred stance for the successful management of this complex condition. Subsequent chapters deal with the pharmacological treatment of mania (Grunze) and depression (Young and Nemeroff ). A summary of treatment guidelines is provided by Yatham and a guide to somatic treatments (electroconvulsive therapy, transcranial stimulation, etc.) by Le Masurier, Herrmann, Coulson and Ebmeier. Psychosocial treatments are ably detailed by Parikh and Velyvis. A number of chapters deal with management in special populations: the elderly (Thomas); women and reproductive issues (Macritchie and Henshaw); and those with physical morbidity (Joseph and Mok). The treatment of BD in the early stages of the illness is reviewed by Garland and Duffy. Anxiety disorders are now recognised as an important feature of BDs, and Chokka and Yeragani expertly review this complex subject. Similarly, substance abuse is reviewed by Goikolea and Vieta. Further chapters cover service delivery (Morriss), psychosocial functioning and quality of life (Michalak and Murray), brain imaging (Ferrier and Lloyd), the practical management of cyclothymia (Perugi and Popovic) and, crucial to the optimal management of this condition, circadian and sleep/wake issues (Murray). There is a review of training issues by Parikh and Michalak, and the book ends with a chapter by Kuan, Curtis and Young, who attempt to integrate the path from neuroscience to clinical practice. We are grateful to all the contributors and thank them all for sharing their expertise with us. This is therefore first and foremost a ‘practical guide’ to the management of BD; we trust that you will find it a useful aid for this fascinating, complex and ever-challenging illness.

References Angst J. (2007). The bipolar spectrum. British Journal of Psychiatry, 190, 189–91. Murray, C.J. & Lopez, A.D. (1997). Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet, 349, 1436–42.

Practical Management of Bipolar Disorder, eds. Allan H. Young, I. Nicol Ferrier and Erin E. Michalak. Published by Cambridge University Press. © Cambridge University Press, 2010.

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Chapter

3

The treatment of mania Heinz Grunze

Introduction

10

Mania is the hallmark of bipolar disorder (BD) and differentiates it from unipolar depression. The Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV-TR; APA, 2000), characterises bipolar I disorder by the occurrence of at least one manic or mixed episode; Table 3.1 and Table 3.2 summarise diagnostic criteria for mania and mixed episodes according to DSM-IV-TR (APA, 2000). By contrast, the International Classification of Diseases, 10th edition (ICD-10; WHO, 2007), differentiates unipolar mania (ICD-10, F30) from bipolar disorder (ICD-10, F31), the latter requiring not only a manic episode, but also at least one episode of major depression. However, as unipolar mania is a rare disorder and is also conceptualised as part of the bipolar spectrum, treatment recommendations given in this chapter imply the assumption of a longterm course with opposing mood deflections. The true complexity of mania, however, is hardly captured by any current categorical classification. Manic states are not monolithic, nor do they always fit into clear clinical distinctions. A wide range of symptoms may occur in an acute manic episode (Table 3.3), with some symptom clusters being more likely than others. The European mania in bipolar longitudinal evaluation of medication (EMBLEM) study (Goetz et al., 2007) found the presence of three major clinical subtypes of patient with acute mania using latent class analysis to define discrete groups of patients. The authors identified: ‘typical mania’ (59% of patients); ‘psychotic mania’ (27%) with more severe mania and presence of psychotic symptoms; and ‘dual mania’ (13%) with a high proportion of substance abuse. These patient groups differed in age of onset, social functioning, service needs and outcome (van Rossum et al., 2008). However, controlled clinical studies usually exclude at least the group of dual mania, which makes it difficult to give substantiated treatment recommendations for all subgroups.

General principles when treating manic patients Treatment of mania requires hospitalisation in most cases, often even emergency treatment and involuntary detention. There may be a few exceptions where manic patients still have sufficient insight and behavioural control to allow treatment in the community, but ensuring sufficient guarding of the patient to minimise risk is often the limiting factor. In addition, having to cope with a manic relative at home may easily devastate any relationship. Advantages of inpatient treatment include risk limitation in a secure environment, professional care around the clock and the opportunity to create a non-stimulating environment. It also allows for more aggressive pharmacotherapy as vital parameters can be monitored and side effects more rapidly recognised and counteracted. Treatment should involve the same humane principles as for any other patient, respecting the patient’s dignity and rights, and hostility as part of a manic syndrome should lead to adaequate safety measures but never provoke a similar response from professionals. Responsible treatment of a manic patient includes the physician taking full responsibility for diagnosis, physical examination, other investigations and explanation of the medical plan of management to the patient and their relatives. The physician should always communicate clearly, understandably and honestly, but calmly, what he or she thinks. Mania is often accompanied by anxiety, and giving the patient the feeling that they are not threatened or getting tricked, but that they are safe, is essential for cooperation and future compliance. Ideally, the manic patient will then consent to treatment. If agreement cannot be reached, it is the task of the responsible psychiatrist to estimate the risks of non-treatment. If there are no other means to avert acute risks to the patient or others, and once a decision has been made to initiate treatment against the patient’s

Practical Management of Bipolar Disorder, eds. Allan H. Young, I. Nicol Ferrier and Erin E. Michalak. Published by Cambridge University Press. © Cambridge University Press, 2010.

Chapter 3: The treatment of mania

Table 3.1 Diagnostic criteria for acute mania according to DSM-IV-TR (APA, 2000) • Criteria for manic episode (DSM-IV-TR, p. 332) • A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week (or any duration if hospitalisation is necessary). • B. During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree: • inflated self-esteem or grandiosity • decreased need for sleep (e.g. feels rested after only 3 hours of sleep) • more talkative than usual, or pressure to keep talking • flight of ideas or subjective experience that thoughts are racing • distractibility (i.e. attention too easily drawn to unimportant or irrelevant external stimuli) • increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation • excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g. engaging in unrestrained buying sprees, sexual indiscretions or foolish business investments). • C. The symptoms do not meet criteria for a Mixed Episode. • D. The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalisation to prevent harm to self or others, or there are psychotic features. • E. The symptoms are not due to the direct physiological effects of a substance (e.g. a drug of abuse, a medication or other treatment) or a general medical condition (e.g. hyperthyroidism).

Table 3.2 Diagnostic criteria for a mixed episode according to DSM-IV-TR (APA, 2000) • A. The criteria are met both for a Manic Episode and for a Major Depressive Episode (except for duration) nearly every day during at least a 1-week period. • B. The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalisation to prevent harm to self or others, or there are psychotic features. • C. The symptoms are not due to the direct physiological effects of a substance (e.g. a drug of abuse, a medication or other treatment) or a general medical condition (e.g. hyperthyroidism).

will, it is important for the staff to act both determinedly and in a skilled way. Every restriction imposed on this occasion on the patient, e.g. constraining mobility or treatment with injections, needs to be constantly scrutinised and to be eased as soon as is justifiable. As soon as a therapeutic alliance has been established, it is the duty of the treating physician to explain to the patient the necessity of these measures. Therapy of mania means primarily treatment with medication in a relaxed, non-stimulating environment. A formal psychotherapeutic approach may be tried additionally when patients have largely recovered and are cooperative, but so far there is little evidence for

its efficacy (Basco & Rush, 1996). Therefore, the focus of the following chapters will be the evidence-based pharmacological treatment modalities of mania.

Dosing and duration of treatment Table 3.4 shows recommended dosages for different antimanic medication in monotherapy, categorised according to their evidence for antimanic efficacy. The dosages are derived from studies in acute mania and do not necessarily reflect the whole dosage range that is approved for a given medication. In the case of combination treatment, a reduction of dosage may be necessary, especially when side effects of two medications are additive or potentiating. In fact, most combination treatment trials used lower dosage of the investigational drug than in the corresponding monotherapy studies. Antimanic treatment should be commenced at least until full remission, syndromal and functional, has been achieved. Persistence of subsyndromal mania is associated with a significantly increased risk of relapse (Tohen et al., 2006). Unless there is doubt regarding whether the manic episode may have been consequent to an external perturbant, e.g. steroids, alcohol or other abusable drugs, all patients should be treated in continuation and maintenance regimens. Most guidelines recommend continuation therapy for 6–12 months

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Chapter 3: The treatment of mania

Table 3.3 Frequency of symptoms observed clinically during acute manic episodes (adapted from Goodwin and Jamison, 2007)

Symptom

Weighted mean (%)

Mood symptoms Irritability

71

Euphoria

63

Depression

46

Lability

49

Expansiveness

60

Cognitive symptoms Grandiosity

73

Flight of ideas, racing thoughts

76

Distractibility, poor concentration

75

Confusion

29

Psychotic symptoms

12

Any delusions

53

Grandiose delusions

31

Persecutory/paranoid delusions

29

Passivity delusions

12

Any hallucinations

23

Auditory hallucinations

18

Visual hallucinations

12

Olfactory hallucinations

15

after remission from an acute mood episode has been achieved; however, this recommendation is based upon expert advice and clinical wisdom, and not derived from controlled studies. Therefore, when selecting a regimen for treatment of acute mania one consideration should be its overall efficacy and tolerability in long-term treatment, thereby minimising switches of medication that may be associated with an increased relapse risk. Treatment should generally be initiated with a medication with a high degree of evidence and good tolerability and safety profile. Previous experience of the patient is helpful in guiding the choice. If this first choice of medication is inefficacious or leads only to partial response, it is unclear how long clinicians should wait before changing or amending medication. In controlled studies, most successful investigational drugs start to separate from placebo within 1 week, and early partial response can predict later response at

Symptom

Weighted mean (%)

Presence or history of psychotic symptoms

61

Thought disorder

19

First rank Schneiderian symptoms

18

Activity and behaviour during mania Hyperactivity

90

Decreased sleep

83

Violent, assaultive behavior

47

Rapid, pressured speech

88

Hyperverbosity

89

Nudity, sexual exposure

29

Hypersexuality

51

Extravagance

32

Religiosity

39

Head decoration

34

Regression (pronounced)

28

Catatonia

24

Faecal incontinence (smearing)

13

study endpoint (Pappadopulos et al., 2008), although response may be delayed with some medications that need titration (e.g. lithium) or are used in lower dosages for tolerability or safety reasons. However, as acute mania constitutes a significant burden to patients and everyone involved, clinicians may not want to wait for too long to tap the last potential of a medication. Hence, in the absence of firm evidence, it may be a rule of thumb that a treatment trial should not last more than 2 weeks, and its continuation or discontinuation should then be decided upon the basis of full, partial or no response (see Figure 3.1).

Monotherapy or skilful polypharmacy? In clinical practice, fewer than 10% of acutely manic patients receive monotherapy; the average number of medications in acutely manic patients is approximately

Chapter 3: The treatment of mania

Table 3.4 Pharmacological and non-pharmacological treatments used in acute mania (in alphabetical order within one category of evidence for efficacy)

Medication

Typically recommended daily dose for adults (variations may occur due to different approvals)

Medication with good evidence of efficacy Aripiprazole

15–30 mg

Asenapine

10–20 mg

Carbamazepine

600–1200 mg (serum level 4–15 mg/l)

Haloperidol

5–20 mg

Lithium

600–1200 mg (serum level 0.8–1.3 mmol/l)

Olanzapine

10–20 mga

Quetiapine

400–800 mg

Risperidone

2–6 mg

Valproate

1200–3000 mg (loading dose 20–30 mg/kg body weight; serum level 75–100 mg/l)

Ziprasidone

80–160 mg

Medication with reasonable evidence of efficacy Chlorpromazine

300–1000 mg

Paliperidone

3–12 mg

Phenytoin

300–400 mg

Pimozide

2–16 mg

Tamoxifen

40–80 mg

Medication with some evidence of efficacy Amisulpride

400–800 mg

Clonazepam

2–8 mg

Clozapine

100–300 mg

Levetiracetam

500–1500 mg

Lorazepam

4–8 mg

Nimodipine

240–480 mg

Oxcarbazepine

900–1800 mg

Retigabine

600–1200 mg

Verapamil

450 mg

Zonisamide

100–500 mg

Zotepine

200–400 mg

Other modalities ECT

Reserved for treatment-refractory mania and special issues (e.g. as alternative option in pregnancy)

a A fixed dose of 20 mg olanzapine was sufficient to demonstrate significant antimanic effects in females with moderate to severe mania (Bech et al., 2006). However, females achieve significantly higher plasma concentrations of olanzapine than males (Kelly et al., 2006). This may imply that higer doses are needed in males with moderate to severe mania (Goodwin & Jamison, 2007).

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Chapter 3: The treatment of mania

First-line medication Choose monotherapy with a medication with well proven efficacy and safety, considering: • symptoms of mania (e.g. euphoric, mixed, psychotic) • previous experience • evidence for efficacy as maintenance treatment if appropriate • modifying medical factors and specific safety profile • route and ease of administration • patient’s preference

Full response after to a2 weeks: continue on medication until full remission has been achieved or beyond, if maintenance treatment is indicated

Partial response after 2 weeks: continue on first-line medication, optimise dosage

No response after 2 weeks: switch to another first-line medication

If no further improvement is observed over the next 3 weeks, consider combination treatment with another first-line medication

If still unresponsive after 2 weeks: consider combination treatment with two first-line treatments

If no or insufficient response: exchange one medication (the potentially less effective one for the actual symptoms) of the combined treatment against another first- or second-line medication

If insufficient or no response: • restart at level 2 or • exchange one medication for another medication including drugs with less firm evidence, if appropriate or • in severe mania: consider clozapine or ECT

Figure 3.1 Treatment algorithm for acute mania, modified from Grunze et al. (2009).

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Chapter 3: The treatment of mania

three (Wolfsperger et al., 2007). This surely underlines the difficulties in treating ‘real world’ patients with severe mania and manifold co-morbidities compared with selected samples in clinical studies – less than 20% of a screened naturalistic patient cohort fulfils all inclusion criteria for entering a randomised, controlled trial. In line with clinical practice results from randomised, controlled trials that show that addition of an antipsychotic drug to patients with manic symptoms despite treatment with lithium or valproate show greater rates of acute efficacy than continuation of lithium or valproate as monotherapy (Smith et al., 2007). Similar beneficial results occurred with a combination of valproate and haloperidol versus haloperidol monotherapy (Müller-Oerlinghausen et al., 2000). So why not recommend combination therapy as a general first-line treatment? Safety and practicability issues clearly favour a first-line approach with monotherapy, making best use of the dosage range available for a given medication. Combined treatments are potentially associated with higher frequency or greater severity of side effects, putting patients at a potentially unnecessary risk and perhaps disrupting the therapeutic alliance. Thus, best use of a diligently chosen monotherapy should be tried before switching to combinatons in order to minimise side effects and medical risks.

Subtype and severity of mania as treatment modifiers Clinical experience with various tentative antimanic agents over recent years has suggested that a drug that is efficacious in one subtype of mania is not necessarily the treatment of choice for the overall spectrum of mania. Controlled studies on antimanic agents have been focused mainly on patients with BD type I disorder and ‘euphoric mania’, resulting in firm evidence that several agents are effective in this type of mania. ‘Dysphoric mania’ describes mania with some depressed and dysphoric features that are either not pronounced enough or insufficiently long lasting to fulfil the criteria for a major depressive episode, whereas ‘mixed states’ imply that diagnostic criteria for a manic episode and a depressive episode (except for the duration criterion) are fulfilled simultaneously. As dysphoric mania and mixed states have not been the sole subjects of prospective controlled trials so far, we have only a limited amount of evidence for efficacy, and even less for the superiority of one drug over another.

Secondary analysis of trials also including mixed patients indicates, for example, that lithium may not be as effective as valproate, carbamazepine, olanzapine or risperidone under these conditions. Although there is no direct evidence for lack of efficacy, the use of typical neuroleptics, especially at a higher dose, may exacerbate dysphoric or depressive symptoms and should probably be avoided in mixed/dysphoric manic states (Tohen et al., 2003). ‘Psychotic mania’ has only recently been arbitrarily designated as a subtype of bipolar mania. It is unclear whether secondary grandiose delusions – the commonest clinical manifestation of ‘psychosis’– merits qualitative distinction, as it looks much more like an expression of severity. However, first-rank symptoms also occur in mania and confuse the distinction from schizophrenia. Psychotic mania has been so little studied in clinical trials that recommendations regarding drug regimens are based principally on inferential criteria. Some evidence suggests higher efficacy of typical neuroleptics than lithium (Johnstone et al., 1988). With the emergence of atypical antipsychotics, monotherapy options may increase, but unambiguous prospective, controlled trials in psychotic mania are still missing. However, post-hoc analysis of Phase III studies of olanzapine, risperidone and ziprasidone showed similar response rates in psychotic versus nonpsychotic mania. Besides symptomatology expressed as (partially aribitrary) subtypes of mania, the severity of behavioural disturbance determines the first-line treatment in acute mania. In clinical practice, severity of mania and speed of onset of action are more likely to be the primary arguments in favour of a particular drug. But unfortunately, no prospective controlled trials are available that specifically look into severly manic patients, defined by, for example, a high threshold on a mania rating scale. Some secondary evidence favours haloperidol over several atypical antipsychotics and lithium in ultra-short-term treatment, but post-hoc subgroup analyses of severly manic patients in randomised, controlled trials also show that risperidone, ziprasidone, aripiprazole and olanzapine are effective in this patient group. Dose-loading with valproate or carbamazepine are suggested alternatives, whereas lithium loading is effective, but associated with higher risks of accidental overdosing (Keck et al., 2000). Finally, electroconvulsive therapy (ECT) is still a valuable last resource in severe delirious mania. On the other end of the severity spectrum, hypomania has also received little attention as far as

15

Chapter 3: The treatment of mania

controlled treatment studies are concerned. Thus, most recommendations are based on clinical wisdom, but not on evidence. If hypomania is well known to be the prelude to mania in an individual patient, treatment should be as for mania. If no further prophylaxis is planned, short-term treatment with either valproate or an atypical antipsychotic may be the best choice, as both are well tolerated, have a good safety profile and a relatively rapid onset of action, minimising the danger that hypomania develops into mania within the next few days. Hypomania may still be approachable to some extent by behavioural interventions in combination with pharmacotherapy. These inventions may centre on modifications of daily routines, e.g. maintaining a natural sleep/wake cycle, stress avoidance and some elements of cognitive behavioural therapy (CBT) (Basco & Rush, 1996).

Medications and other modalities in the treatment of mania The following review of different medications is based on a literature search, including the FDA Clinical trial database (www.clinicaltrials.gov]), up to January 2009. However, with the rapid progress in this area, there is always a chance that some evidence – especially negative evidence from failed and hitherto unpublished trials – may have been missed.

Lithium

16

Lithium has clearly the largest pool of studies in mania, with more than 20 published or presented studies of varying quality, starting with Shou’s work in 1954 (Schou et al., 1954). But only more recent studies, beginning with a three-arm study comparing valproate and lithium against placebo (Bowden et al., 1994), can be considered to reach the current methodological standards for a drug-approval study. Since then, several well-designed and placebo-controlled studies have repeatably confirmed lithium’s antimanic efficacy. A recent meta-analysis of six randomised, controlled trials with lithium in acute mania (four of them published, and two as part of a registration dossier) revealed an overall standardised effect size of 0.40 (95% CI: 0.28, 0.53) and an overall ‘numbers needed to treat’ (NNT) for response of 6 (95% CI: 4, 13) (Storosum et al., 2007). The antimanic efficacy of lithium may be higher in pure (euphoric) mania than in mania with concomitant dysphoric or depressive features (Swann et al., 1997). In methodologically less sophisticated comparator studies, lithium was tested against various antipsychotics,

including chlorpromazine, haloperidol, olanzapine and risperidone, and against carbamazepine. Overall, these studies showed largely similar efficacy of lithium and the respective comparator. Target plasma levels for lithium in recent controlled studies were usually in the range of 0.6 to 1.3 mmol/l. In clinical practice, adolescents and young adults may require and tolerate plasma levels at the higher end of this range, whereas elderly patients may tolerate dosages only at the lower end of this range. A slower onset of action of lithium, relative to the investigational drug, has been observed in some studies (e.g. Keck et al., 2009), but not in others (e.g. Bowden et al., 2005). This potentially slower onset of action together with the absence of sedative properties often makes it necessary to combine it with a tranquilising agent at treatment initiation. Lithium is not suitable with certain medical conditions, which should be excluded before treatment initiation, e.g. renal problems or thyroid dysfunction. The usefulness of lithium in acute mania may also be limited by the need for regular plasma level checks to avoid toxicity, its side-effect profile and other contraindications. These limitations have been dealt with extensively in standard textbooks.

Anticonvulsants Carbamazepine Starting with the first studies of Okuma et al. (1973), carbamazepine has been tested in acute mania in several small comparator studies against the conventional antipsychotics, lithium and valproate. The impression of these studies was that carbamazepine was overall equally effective as comparators, with a probably slightly slower onset of response compared with antipsychotics and valproate, but slightly faster acting than lithium (Grunze, 2006). Two large randomised, placebo-controlled mania studies with carbamazepine as the investigational drug were published just a few years ago (Owen, 2006), proving the significant superiority of carbamazepine. Looking into specific subgroups of patients, carbamazepine may be especially helpful in patients with incomplete response to lithium in acute mania, rapidcycling and co-morbid organic (neurological) disorders, and schizoaffective patients (Grunze, 2006). Common side effects of carbamazepine include oversedation and blurred vision, especially with high dosages and rapid titration. Tolerability isssues may be less problematic with extended-release formulations.

Chapter 3: The treatment of mania

Rare, but potentially severe, side effects include allergic reactions, lupus erythematosus, agranulocytosis and hyponatraemia. Detailed information on the tolerability and safety profile of carbamazepine is available in recent reviews. In addition, carbamazepine is associated with an increased risk of birth defects (Morrow et al., 2006). The main shortcoming of carbamazepine, however, is its manifold interactions with other psychotropic medication, including several antipsychotics, antidepressants and anticonvulsants (Spina et al., 1996). As most patients with acute mania are treated with several medications, this clearly limits the utility of carbamazepine.

Valproate This chapter uses ‘valproate’ as a common generic name for the different preparations tested in acute mania, e.g. valproic acid, sodium valproate, divalproate, divalproex sodium and valpromide. As far as pharmacokinetics and pharmacodynamics are concerned, only valproic acid finally reaches and penetrates the blood– brain barrier. Although tolerability is enhanced with extended-release preparations, the differences do not warrant grouping valproic acid derivatives as different medications. Several placebo-controlled studies have provided consistent evidence that valproate is an efficacious treatment for acute mania (Macritchie et al., 2003). Valproate also showed similar efficacy in comparator trials with lithium, carbamazepine, haloperidol, and in one study against olanzapine, but not in two others. Dose loading with 20–30 mg/kg body weight seems to be more effective in mania than slower titration schemes (Hirschfeld et al., 2003), and plasma levels of 75–99 mg/l seem to be associated with the best efficacy/ tolerability ratio (Allen et al., 2006). The safety margin of valproate is relatively large, allowing rapid titration and a subsequent earlier onset of action. Tolerability of valproate appears fair across trials. Gastointestinal discomfort, sedation and tremor are more frequently observed with valproate than with placebo in most trials, but usually do not result in higher discontinuation rates. For rare, but severe, complications such as hepatic failure, pancreatitis or hyperammonaemic coma and precautionary measures please refer to the pertinent reviews (e.g. Haddad et al., 2009). Valproate is not appropriate in some medical conditions, e.g. liver disease, and in combination with some medications, e.g. warfarin. Caution should be used in women of childbearing age, not only because of teratogenicity, but also because of the supposed

increased risk of polycystic ovary syndrome (Rasgon et al., 2005).

Other anticonvulsants with potential antimanic properties Several medications have been proposed as having antimanic properties, but none of them has been studied enough to allow the conclusion that efficacy and tolerability were within the same range as the anticonvulsants previously reviewed in detail. Phenytoin has demonstrated antimanic properties in a small, double-blind, placebo-controlled add-on study to haloperidol (Mishory et al., 2000). The side effect profile of phenytoin, especially cognitive side effects and cerebellar atrophy, however, makes it a medication of subordinate choice for acute mania. For oxcarbazepine, a recent review of several small, underpowered or not placebo-controlled studies came to the conclusion that it may be useful in treating manic symptoms (Popova et al., 2007), but conclusive evidence is lacking. Other anticonvulsants with evidence only from open studies, but not from controlled trials, include levetiracetam, zonisamide and retigabine. Negative evidence – failure to separate from placebo in controlled trials – exists for topiramate, gabapentin and lamotrigine. For tiagabine, open studies were suggestive of no efficacy together with an increased risk of epileptiform seizures.

Atypical antipsychotics The treatment choice in acute mania has significantly widened with the emergence of the atypical antipsychotics. In this chapter we first list the different antipsychotics that were approved for the treatment of mania at the end of 2008, and then we will briefly touch on other atypicals that may be of clinical interest in this indication. Medications are listed in alphabetical order; it does not reflect true or assumed superiority of one atypical over another.

Aripiprazole Four placebo-controlled acute mania studies have been published so far, one of them also including lithium (Keck et al., 2009) and another one haloperidol as a comparator (Young et al., 2009). In a placebo-controlled combination treatment study with either valproate or lithium, aripiprazole was also superior to valproate or lithium alone (Vieta et al., 2008c). In addition, an intramuscular injectable preparartion of aripiprazole has demonstrated antimanic efficacy (Sanford & Scott, 2008).

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Chapter 3: The treatment of mania

Secondary analyses confirmed the broad-spectrum of efficacy of aripiprazole across subtypes of mania. Headache, somnolence and dizziness were the most frequently reported side effects, but none was significantly more frequent than with placebo. However, akathisia appears to be more frequent with aripiprazole than with placebo. No significant QTc changes or elevations in prolactin, cholesterol and fasting blood glucose levels were reported for aripiprazole.

Olanzapine

18

Together with lithium, olanzapine is probably the most extensively studied medication for acute mania. It has shown significant superiority over placebo in five double-blind placebo-controlled monotherapy studies, including one in adolescent mania (Tohen et al., 2007). When olanzapine was combined with lithium or valproate, these combinations were also more effective than valproate or lithium alone (Tohen et al., 2004). In all these studies, olanzapine showed comparable efficacy across subtypes of mania. In addition, a randomised, controlled trial of injectable olanzapine in agitated mania has demonstrated significant superiority of olanzapine against placebo and lorazepam after 2 h (Meehan et al., 2001). Intramuscular injections of olanzapine, however, bear an increased risk of respiratory arrest when patients are on concomitant benzodiazepines. Several head-to-head comparison studies with olanzapine have also been conducted. Whereas efficacy of olanzapine appeared slightly higher than that of valproate or lithium, olanzapine-treated subjects were also more prone to side effects, limiting clinical utility. Compared with risperidone, no difference in antimanic efficacy was observed (Perlis et al., 2006), wheras in another trial haloperidol was significantly more efficacious than olanzapine after 6 weeks (Tohen et al., 2003). These positive results in controlled clinical studies are also consistent with a large, pan-European naturalistic mania study (EMBLEM), which reported efficacy both for olanzapine monotherapy and olanzapine in combination with other medications in a broad spectrum of manic patients (Vieta et al., 2008b). As far as tolerability and safety are concerned, oral olanzapine showed a favourable profile regarding short-term treatment. Somnolence and dizziness were associated significantly more frequently with olanzapine treatment than with placebo. Anticholinergic side effects such as dry mouth, constipation or extrapyramidal side effects (EPS) occurred rarely in the controlled

studies. However, already in short-term trials the mean weight gain from baseline to endpoint ranged from 1.65 to 4 kg, and metabolic issues clearly complicate the intermediate and long-term treatment with olanzapine (Franciosi et al., 2005).

Quetiapine Four randomised, placebo-controlled acute mania monotherapy studies have been conducted (Bowden et al., 2005; McIntyre et al., 2005; Cutler et al., 2008; Vieta et al., 2008a) demonstrating antimanic efficacy of quetiapine. Whereas quetiapine was in one of these studies as effective as lithium, haloperidol showed a faster onset of action and better efficacy than quetiapine in another trial (Scherk et al., 2007). These controlled studies concentrated only on euphoric mania, so it is not possible to make conclusions about mixed or psychotic mania. Quetiapine was also tested in two placebo-controlled combination studies as an add-on to lithium or valproate, with one of them demonstrating superiority of the combination quetiapine/lithium or valproate. Quetiapine also appears to be effective and safe in adolescents, as demonstrated by two controlled studies. The tolerability of quetiapine throughout studies appears good, with the exception of somnolence, which was two- to sixfold greater than with placebo. In addition, mean weight gain was consistently higher in quetiapine-treated patients compared with placebo, haloperidol or lithium. As with olanzapine, metabolic issues may become more prominent when quetiapine is taken as long-term medication but appear not to be of significance for short-term use.

Risperidone Three double-blind, placebo-controlled monotherapy trials have been published so far, one of them also having a comparator arm with haloperidol. Risperidone was in all studies significantly better than placebo, and comparison against haloperidol showed no difference in antimanic efficacy (Scherk et al., 2007). There is evidence for good efficacy in severe and psychotic mania from one study (Khanna et al., 2005), but a lack of controlled data supporting the use of risperidone in mixed mania. Two placebo-controlled studies investigated risperidone as an add-on to valproate or lithium and as an add-on to lithium, valproate or carbamazepine. Whereas the first study demonstrated superiority of the risperidone add-on, the second one failed due to

Chapter 3: The treatment of mania

lack of response in the patients receiving carbamazepine as primary treatment. This illustrates the problematic issues associated with carbamazepine as an inducer of the cytochrome P450 enzyme in combination treatment. Higher dosages of risperidone (6 mg/day) were associated in one study with an increased rate of EPS, whereas in lower dosages, as applied in the other studies, discontinuation of risperidone due to EPS was similar to placebo. Two studies reported higher rates of somnolence, and also dizziness occurred slightly more often with risperidone than with placebo. The mean weight gain ranged from 1.7 to 2.4 kg at endpoint, and the observed elevation of prolactin in blood was even higher than with haloperidol in one study (Smulevich et al., 2005). This may be because of the relatively low brain penetration of risperidone and the relatively high plasma levels required for efficacy: these preferentially elevate prolactin because the pituitary lies outside the blood–brain barrier.

Ziprasidone Ziprasidone monotherapy demonstrated antimanic efficacy in three double-blind placebo-controlled studies. Post-hoc analyses of these trials also supplied evidence that ziprasidone is effective in dysphoric/mixed states and psychotic mania (Greenberg & Citrome, 2007). Ziprasidone is also available as intramuscular injectable solution. In a placebo-controlled add-on study to lithium or valproate, ziprasidone did not separate from placebo at endpoint, although it enhanced antimanic response at the beginning. No significant differences compared with placebo were observed in EPS-related scales, but cases of akathisia were numerically more frequent in one study. In addition, initial somnolence was reported about three to four times as often for ziprasidone when compared with placebo. Of some concern is the cardiovascular safety profile of ziprasidone, although no QTc prolongation beyond 500 ms was observed in the cited mania studies, and the main safety concern – torsades de pointes – has also not been reported in post-marketing surveillance. Ziprasidone and aripiprazole are the two atypical antipsychotics licensed for bipolar disorder (but not in all countries) that may be largely weight neutral.

Other atypical antipsychotics used off label in mania Amisulpride is a frequently used antimanic medication in some parts of the world, but evidence from controlled studies is still vague and disputable (Thomas et al.,

2008). Amisulpride is not associated with weight gain. However, high dosages of amisulpride usully administered in acute mania do cause hyperprolactinaemia. For asenapine, two placebo-controlled acute mania monotherapy trials and one add-on study to lithium or valproate have been presented in scientific meetings as posters so far. In all three studies, asenapine demonstrated significant superiority over placebo and was well tolerated; in particular, the incidence of EPS was low. Limited data, however, suggest that asenapine may be associated with weight gain and metabolic issues. Licensing for mania is still pending but may have been granted by the time this book is published. Numerous case reports and several small investigator-initiated trials support the antimanic as well as mild antidepressive and good prophylactic efficacy of clozapine in bipolar patients, making it a last-resort drug in treatment-refractory bipolar patients (Gitlin, 2006). Large-scale methodologically unambiguous studies, however, are missing because of the lack of commercial interest and the potentially life-threatening side effects of clozapine. More recently, paliperidone (an active metabolite of risperidone) has been tested in two placebo-controlled monotherapy trials, one of them positive and another one reaching significance only for the highest dose of paliperidone (12 mg/day). Similarly to asenapine, a licence for mania had not been granted by the end of 2008. The situation with zotepine is similar to that of clozapine. At least two open studies are in line with antimanic efficacy, but a lack of commercial interest has prohibited further evaluation in randomised, controlled studies. As zotepine is capable of causing significant weight gain, its value may be limited with the emergence of weight-neutral atypicals with proven antimanic efficacy.

Typical neuroleptics Haloperidol Haloperidol has been the primary clinical choice in severe mania for decades, but a sound scientific basis for this use has been produced only recently, when it has served as a comparator in randomised, placebo-controlled studies of atypical antipsychotics (Cipriani et al., 2006; Scherk et al., 2007). The usefulness of haloperidol, however, is clearly limited by its high propensity to induce acute extrapyramidal motor symptoms at established doses and – probably even more importantly – tardive dyskinesia. Nevertheless,

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Chapter 3: The treatment of mania

at least in the emergency treatment of severe mania or in patients who do not respond to other therapies, haloperidol has its place and justification. Doses of haloperidol chosen in the past may have been unnecessarily high, and lower dosages may have the same efficacy with less side-effect burden (Rifkin et al., 1994). Low doses of haloperidol still lead to sufficient D2 receptor occupancy which, in turn, predicts antimanic efficacy (Harrison-Read, 2009). Thus, low-dose typical neuroleptics may still be a sensible alternative to atypical antipsychotics in selected patients, and this may apply as much to mania as it does to schizophrenia.

Chlorpromazine Only one placebo-controlled randomised trial for chlorpromazine has been reported in acutely manic patients. Further evidence stems from head-to-head comparisons versus lithium, carbamazepine, pimozide, thiothixene and ECT. Doses established for use in acute mania (200–800 mg/day) are associated with a high risk of EPS, and similar considerations apply to the use of chlorpromazine as to haloperidol. Other frequent side effects with chlorpromazine include pronounced sedation, tardive dyskinesia, hypersensitivity of the skin to sunlight and hepatotoxicity.

Benzodiazepines Clonazepam and lorazepam are quite frequently used in bipolar disorder – lorazepam particularly as a rescue medication. However, they are usually not considered as primary mood-stabilising agents. Nevertheless, there are some studies supporting antimanic effects of these two drugs (Grunze, 2004), although their addictive potential should deter psychiatrists from using them as primary and long-term treatment (Chouinard, 2004).

Experimental medications

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Three placebo-controlled studies gave evidence for the antimanic efficacy of the protein kinase C inhibitor tamoxifen, although some methodological issues may impact on the generalisability of the result (Tohen, 2008). Tamoxifen was well tolerated, but its nature as an anti-oestrogen may raise some concerns for longerterm treatment. The evidence for the calcium antagonists nimodipine and verapamil is limited and partly contradictory. The viability of these calcium antagonists is also limited because of the effect on blood pressure (verapamil) and a short half-life necessitating multiple dosing per day (nimodipine).

Electroconvulsive therapy (ECT) No randomised, controlled studies have been conducted for ECT in mania, but numerous case reports and chart reviews support the utility of ECT in severe mania. A comprehensive review of open studies and case reports describes improvement in approximately 80% of manic patients (Mukherjee et al., 1994) – thus greater than for any pharmacological intervention. ECT is still a valuable last resource in severe mania that is otherwise treatment refractory (Karmacharya et al., 2008). Recent work suggests that bifrontal ECT is at least as efficacious as bitemporal ECT in severe mania and, at the same time, better tolerated (Barekatain et al., 2008).

Conclusions Skilful treatment of mania will remain a clinical challenge, although treatment options have significantly increased over recent years, and new targets for drug development will emerge. Protein kinase C inhibition is one example of a mechanism with some recent evidence of efficacy. However, with the substantial number of medications available, it will become more essential that any new medication shows additional benefits besides being a pure antimanic agent. Most clinicians are likely to prefer antimanic drugs that also have established long-term prophylactic efficacy not only against manic relapse, but also against depressive episodes, or – even more challenging – substances that also have antidepressant activity. With the expanding range of drugs with evidence of efficacy in mania, psychiatrists as well as patients may reasonably place safety, tolerability and evidence of good persistence over time on equal footing with efficacy in selecting and continuing a regimen. Similarly, tolerability and ease of adhering to the prescribed dosage can benefit from selection of drug formulations with extended-release properties and/or once daily dosing. In a highly competitive field, future research and development will have to take that into account at an earlier stage than in the past; it will not be enough if you have ‘just another antimanic drug’ to be clinically accepted.

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APA (2000). The Diagnostic and Statistical Manual of Mental Disorders, 4th edition. Arlington, VA: American Psychiatric Association. www.psychiatryonline. com/resourceTOC.aspx?resourceID=1 [accessed 23 December 2009]. Barekatain, M., Jahangard, L., Haghighi, M., et al. (2008). Bifrontal versus bitemporal electroconvulsive therapy in severe manic patients. Journal of ECT, 24, 199–202. Basco, M.R. & Rush, A.J. (1996). Cognitive Behavioral Therapy for Bipolar Disorder. New York: Guildford Press. Bech, P., Gex-Fabry, M., Aubry, J.M., et al. (2006). Olanzapine plasma level in relation to antimanic effect in the acute therapy of manic states. Nordic journal of psychiatry, 60, 181–2. Bowden, C.L., Brugger, A.M., Swann, A.C., et al. (1994). Efficacy of divalproex vs lithium and placebo in the treatment of mania. The Depakote Mania Study Group. JAMA: Journal of the American Medical Association, 271, 918–24. Bowden, C.L., Grunze, H., Mullen, J., et al. (2005). A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder. Journal of Clinical Psychiatry, 66, 111–21. Chouinard, G. (2004). Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound. Journal of Clinical Psychiatry, 65 (Suppl. 5), 7–12. Cipriani, A., Rendell, J.M. Geddes, J.R. (2006). Haloperidol alone or in combination for acute mania. Cochrane Database of Systematic Reviews, 3, CD004362. Cutler, A.J., Datto, C., Nordenhem, A., et al. (2008). Effectiveness of extended release formulation of quetiapine as montherapy for the treatment of acute bipolar mania (trial D144CC00004). International Journal of Neuropsychopharmacology / Official Scientific Journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 11 (Suppl. 1), 184. Franciosi, L.P., Kasper, S., Garber, A.J., et al. (2005). Advancing the treatment of people with mental illness: a call to action in the management of metabolic issues. Journal of Clinical Psychiatry, 66, 790–8. Gitlin, M. (2006). Treatment-resistant bipolar disorder. MolecularPsychiatry, 11, 227–40. Goetz, I., Tohen, M., Reed, C., et al. (2007). Functional impairment in patients with mania: baseline results of the EMBLEM study. Bipolar Disorders, 9, 45–52. Goodwin, F.K. & Jamison, K.R. (2007). Manic-depressive illness, 2nd edition. New York: Oxford University Press. Greenberg, W. M. & Citrome, L. (2007). Ziprasidone for schizophrenia and bipolar disorder: a review of the clinical trials. CNS.Drug Reviews, 13, 137–77.

Grunze, H. (2004). Other agents for bipolar disorder. In: Akiskal, H.S. & Tohen, M. (Eds). Innovative Bipolar Pharmacotherapy. Philadelphia, PE: Lippincott. Grunze, H. (2006). Carbamazepine, other anticonvulsants and augmenting agents. In: Akiskal, H.S. & Tohen, M. (Eds). Bipolar Psychopharmacotherapy: Caring for the Patient. Chichester: John Wiley & Sons. Grunze, H., Vieta, E., Goodwin, G.M., et al. (2009). The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: update 2009 on the treatment of acute mania. World Journal of Biological Psychiatry, 10, 85–116. Haddad, P.M., Das, A., Ashfaq, M., et al. (2009). A review of valproate in psychiatric practice. Expert Opinion on Drug Metabolism & Toxicology, 5, 539–51. Harrison-Read, P. (2009). Antimanic potency of typical neuroleptic drugs and affinity for dopamine D2 & serotonin 5-HT2A receptors – a new analysis of data from the archives and implications for improved antimanic drug treatments. Journal of Psychopharmacology, 8, 899–907. Epub 2008 Jul 17. Hirschfeld, R.M., Baker, J.D., Wozniak, P., et al. (2003). 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. Journal of Clinical Psychiatry, 64, 841–6. Johnstone, E.C., Crow, T.J., Frith, C.D., et al. (1988). The Northwick Park “functional” psychosis study: diagnosis and treatment response. Lancet, 2, 119–25. Karmacharya, R., England, M.L., Ongur, D. (2008). Delirious mania: clinical features and treatment response. Journal of Affective Disorders, 109, 312–16. Keck, P.E., McElroy, S.L., Bennett, J.A. (2000). Pharmacologic loading in the treatment of acute mania. Bipolar Disorders, 2, 42–6. Keck, P.E., Orsulak, P.J., Cutler, A.J., et al. (2009). Aripiprazole monotherapy in the treatment of acute bipolar I mania: a randomized, double-blind, placeboand lithium-controlled study. Journal of Affective Disorders, 112, 36–49. Kelly, D.L., Richardson, C.M., Yu, Y., et al. (2006). Plasma concentrations of high-dose olanzapine in a doubleblind crossover study. Human Psychopharmacology, 21, 393–8. Khanna, S., Vieta, E., Lyons, B., et al. (2005). Risperidone in the treatment of acute mania: double-blind, placebocontrolled study. British Journal of Psychiatry, 187, 229–34. Macritchie, K., Geddes, J.R., Scott, J., et al. (2003). Valproate for acute mood episodes in bipolar disorder. Cochrane Database of Systematic Reviews, 1, CD004052. McIntyre, R.S., Brecher, M., Paulsson, B., et al. (2005). Quetiapine or haloperidol as monotherapy for bipolar

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mania – a 12-week, double-blind, randomised, parallel-group, placebo-controlled trial. European Neuropsychopharmacology, 15, 573–85. Meehan, K., Zhang, F., David, S., et al. (2001). A doubleblind, randomized comparison of the efficacy and safety of intramuscular injections of olanzapine, lorazepam, or placebo in treating acutely agitated patients diagnosed with bipolar mania. Journal of Clinical Psychopharmacology, 21, 389–97. Mishory, A., Yaroslavsky, Y., Bersudsky, Y., et al. (2000). Phenytoin as an antimanic anticonvulsant: a controlled study. American Journal of Psychiatry, 157, 463–5. Morrow, J., Russell, A., Guthrie, E., et al. (2006). Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. Journal of Neurology, Neurosurgery, and Psychiatry, 77, 193–8. Mukherjee, S., Sackeim, H.A., Schnur, D.B. (1994). Electroconvulsive therapy of acute manic episodes: a review of 50 years’ experience. American Journal of Psychiatry, 151, 169–76. Müller-Oerlinghausen, B., Retzow, A., Henn, F., et al. (2000). Valproate as an adjunct to neuroleptic medication for the treatment of acute episodes of mania. A prospective, randomized, double-blind, placebo-controlled multicenter study. Journal of Clinical Psychopharmacology, 20, 195–203. Okuma, T., Kishimoto, A., Inoue, K., et al. (1973). Antimanic and prophylactic effects of carbamazepine (Tegretol) on manic depressive psychosis. A preliminary report. Folia Psychiatrica et Neurologica Japonica, 27, 283–97. Owen, R.T. (2006). Extended-release carbamazepine for acute bipolar mania: a review. Drugs of Today, 42, 283–9. Pappadopulos, E., Vieta, E., Mandel, F. (2008). Day 4 partial resonse to ziprasidone predicts later treatment response in patients with bipolar disorder. European Neuropsychopharmacology, 18 (Suppl. 4), 443. Perlis, R.H., Baker, R.W., Zarate Jr, C.A., et al. (2006). Olanzapine versus risperidone in the treatment of manic or mixed states in bipolar I disorder: a randomized, double-blind trial. Journal of Clinical Psychiatry, 67, 1747–53. Popova, E., Leighton, C., Bernabarre, A., et al. (2007). Oxcarbazepine in the treatment of bipolar and schizoaffective disorders. Expert Review of Neurotherapeutics, 7, 617–26. Rasgon, N.L., Altshuler, L.L., Fairbanks, L., et al. (2005). Reproductive function and risk for PCOS in women treated for bipolar disorder. Bipolar Disorders, 7, 246–59. Rifkin, A., Doddi, S., Karajgi, B., et al. (1994). Dosage of haloperidol for mania. British Journal of Psychiatry, 165, 113–16.

Sanford, M. & Scott, L.J. (2008). Intramuscular aripiprazole: a review of its use in the management of agitation in schizophrenia and bipolar I disorder. CNS Drugs, 22, 335–52. Scherk, H., Pajonk, F.G., Leucht, S. (2007). Secondgeneration antipsychotic agents in the treatment of acute mania: a systematic review and meta-analysis of randomized controlled trials. Archives of General Psychiatry, 64, 442–55. Schou, M., Juel-Nielsen, N., Strömgren, E., et al. (1954). The treatment of manic psychoses by the administration of lithium salts. Journal of Neurology, Neurosurgery, and Psychiatry, 17, 250–60. Smith, L.A., Cornelius, V., Warnock, A., et al. (2007). Acute bipolar mania: a systematic review and meta-analysis of co-therapy vs. monotherapy. Acta Psychiatrica Scandinavica, 115, 12–20. Smulevich, A.B., Khanna, S., Eerdekens, M., et al. (2005). Acute and continuation risperidone monotherapy in bipolar mania: a 3-week placebo-controlled trial followed by a 9-week double-blind trial of risperidone and haloperidol. European Neuropsychopharmacology, 15, 75–84. Spina, E., Pisani, F., Perucca, E. (1996). Clinically significant pharmacokinetic drug interactions with carbamazepine. An update. Clinical pharmacokinetics, 31, 198–214. Storosum, J.G., Wohlfarth, T., Schene, A., et al. (2007). Magnitude of effect of lithium in short-term efficacy studies of moderate to severe manic episode. Bipolar Disorders, 9, 793–8. Swann, A.C., Bowden, C.L., Morris, D., et al. (1997). Depression during mania. Treatment response to lithium or divalproex. Archives of General Psychiatry, 54, 37–42. Thomas, P., Vieta, E.: SOLMANIA study group (2008). Amisulpride plus valproate vs haloperidol plus valproate in the treatment of acute mania of bipolar I patients: a multicenter, open-label, randomized, comparative trial. Neuropsychiatric disease and treatment, 4, 675–86. Tohen, M. (2008). Clinical trials in bipolar mania: implications in study design and drug development. Archives of General Psychiatry, 65, 252–3. Tohen, M., Bowden, C.L., Calabrese, J.R., et al. (2006). Influence of sub-syndromal symptoms after remission from manic or mixed episodes. British Journal of Psychiatry, 189, 515–19. Tohen, M., Chengappa, K., Suppes, T., et al. (2004). Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabiliser v. mood stabiliser alone. British Journal of Psychiatry, 184, 337–45. Tohen, M., Goldberg, J.F., Gonzalez-Pinto Arrillaga, A.M., et al. (2003). A 12-week, double-blind comparison of

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olanzapine vs haloperidol in the treatment of acute mania. Archives of General Psychiatry, 60, 1218–26. Tohen, M., Kryzhanovskaya, L., Carlson, G., et al. (2007). Olanzapine versus placebo in the treatment of adolescents with bipolar mania. American Journal of Psychiatry, 164, 1547–56. van Rossum, I., Haro, J.M., Tenback, D., et al. (2008). Stability and treatment outcome of distinct classes of mania. European Psychiatry, 23, 360–7. Vieta, E., Berwaerts, J., Nuamah, I., et al. (2008a). Randomised, placebo, active-controlled study of paliperidone extended-release (ER) for acute manic and mixed episodes in bipolar I disorder. European Neuropsychopharmacology, 18 (Suppl. 4), S369. Vieta, E., Panicali, F., Goetz, I., et al. (2008b). Olanzapine monotherapy and olanzapine combination therapy in the treatment of mania: 12-week results from the European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM) observational study. Journal of Affective Disorders, 106, 63–72.

Vieta, E., Tjoen, C., McQuade, R.D., et al. (2008c). Efficacy of adjunctive aripiprazole to either valproate or lithium in bipolar mania patients partially nonresponsive to valproate/lithium monotherapy: a placebo-controlled study. American Journal of Psychiatry, 165, 1316–25. WHO (2007). International Classification of Diseases, 10th edition. Geneva: World Health Organization. http:// apps.who.int/classifications/apps/icd/icd10online/ [accessed 14 December 2009]. Wolfsperger, M., Greil, W., Rossler, W., et al. (2007). Pharmacological treatment of acute mania in psychiatric in-patients between 1994 and 2004. Journal of Affective Disorders, 99, 9–17. Young, A.H., Oren, D.A., Lowy, A., et al. (2009). Aripiprazole monotherapy in acute mania: 12-week randomised placebo- and haloperidol-controlled study. British Journal of Psychiatry, 194, 40–8.

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4

Pharmacological treatment of bipolar depression Allan H. Young and Charles B. Nemeroff

Introduction The practical management of bipolar depression represents one of the greatest challenges for the clinician concerned with the treatment of this illness. As discussed elsewhere in this book, bipolar disorder (BD) is common, and much of the considerable disability associated with this illness is due to the depressed phase (Post et al., 2003); patients with bipolar depression have significant psychosocial impairment (Michalak et al., 2008). In addition to this predominant depression, patients suffer higher mortality rates than other bipolar patients, and depression is a major risk factor for suicide in BD (Angst et al., 2005). Pharmacotherapy is the mainstay of treatment, although both psychological and somatic treatment strategies may also be utilised. This chapter will briefly outline the evidence base for current pharmacotherapeutic practice. For a more extensive discussion and specific treatment recommendations, the reader is referred to more comprehensive reviews (Calabrese et al., 2009; Young & Nemeroff, 2009).

Pharmacotherapy: focus on bipolar disorder type I depression Lithium

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A review of the older literature revealed that lithium was significantly more effective than placebo for the treatment of bipolar depression, and approximately half of the patients experienced a relapse of depressive symptoms when lithium was substituted by placebo (Srisurapanont et al., 1995). However, a more recent double-blind, randomised, placebo-controlled study of quetiapine and lithium as acute monotherapy treatment for bipolar depression found no statistically significant difference between lithium and placebo (Young et al., 2010). The mean serum lithium level in this study was 0.61 mEq/l (mmol/l), and it is unknown if response rates would be improved with higher serum lithium levels for a longer duration than the 8 weeks’ duration of this trial.

Meta-analyses of trials of lithium in patients with BD include further data concerning the use of lithium as a maintenance treatment (Geddes et al., 2004; Smith et al., 2007). Lithium was shown in these analyses to be more effective than placebo in preventing any new mood episodes. However, although lithium was superior to placebo in preventing manic episodes, this was not clearly shown for depressive episodes (Geddes et al., 2004; Smith et al., 2007). Overall, therefore, the evidence for lithium being antidepressant in BD seems less clear cut than that for its antimanic actions.

Lamotrigine monotherapy Lamotrigine was initially examined in a double-blind, placebo-controlled study of lamotrigine monotherapy for the acute treatment of BD type I depression (Calabrese et al., 2000). More recently, this study was included in a review of five double-blind, placebocontrolled trials, all of which assessed the efficacy of lamotrigine in the acute treatment of bipolar depression (Calabrese et al., 2008). Although there is a widespread belief that lamotrigine is antidepressant in BD, the overall pooled effect was modest at best. The advantage of lamotrigine over placebo was greater in the more severely depressed participants, and the slow dose titration necessary to minimise the risk of dangerous rashes may mitigate against an antidepressant effect fully manifesting in the time frame of acute treatment studies. Two longer-term studies compared the effectiveness of lithium and lamotrigine monotherapy over a period of 18 months in 638 patients with BD type I and recent episodes of mania or depression (Bowden et al., 2003; Calabrese et al., 2003). Bowden and colleagues demonstrated that lamotrigine was significantly more effective than placebo at prolonging the time to intervention for a depressive episode (Bowden et al., 2003). Calabrese and co-workers also found that lamotrigine significantly prolonged time to a depressive episode (Calabrese et al., 2003). A pooled analysis of data from

Practical Management of Bipolar Disorder, eds. Allan H. Young, I. Nicol Ferrier and Erin E. Michalak. Published by Cambridge University Press. © Cambridge University Press, 2010.

Chapter 4: Pharmacological treatment of bipolar depression

these trials showed that lamotrigine, but not lithium, was superior to placebo at delaying the time to intervention for a depressive episode (Goodwin et al., 2004). Lamotrigine is therefore typically used for prevention of depressive relapse in BD, although this is likely to be most effective in patients who have some history of lamotrigine responsiveness.

Adjunctive lamotrigine The use of adjunctive lamotrigine for bipolar depression was recently evaluated in an 8-week, double-blind, randomised, placebo-controlled trial; the results showed that lamotrigine in combination with lithium was superior to lithium monotherapy (van der Loos et al., 2009). However, a Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study of open-label lamotrigine, inositol or risperidone as adjuncts to a mood stabiliser for up to 16 weeks in patients (n=66) with treatment-resistant BD type I or type II depression found no significant between-group differences (Nierenberg et al., 2006). A comparison of the adjunctive use of lamotrigine and lithium in the long-term treatment of BD was carried out in an open, randomised trial (Licht, 2008). Patients were randomised to receive lithium (dosed to attain serum levels of 0.5–0.8 mmol/l, n=78) or lamotrigine (up to 400 mg/d, n=77) for up to 6 years, with concomitant pharmacologic therapy allowed for the first 6 months of the study period. No differences were noted between lamotrigine and lithium when used as adjunctive therapy with respect to the primary outcome measure (Licht, 2008).

Valproate A small 8-week, double-blind, placebo-controlled, randomised study that evaluated the clinical efficacy of valproate (as divalproex; up to 2500 mg/d) in 25 outpatients with BD type I depression found that the active treatment was significantly more effective than placebo in improving symptoms of depression (Davis et al., 2005). Further evidence is provided by a very small double-blind, randomised study in which patients with BD type I depression (n=9) received divalproex or placebo for 6 weeks (Ghaemi et al., 2007). Divalproex was associated with a significantly greater reduction in Montgomery–Asberg depression rating scale (MADRS) total score, the primary efficacy measure, from baseline to Week 6 compared with placebo (P