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“In the past decade or so, not only has there been a better awareness of psychiatric disorders, but increasingly larger numbers of people are seeking help for these conditions. There is indeed a better focus on personalised psychiatry and pharmacological research. With further recent advances in innovations and better medications, practice of clinical psychiatry is changing with greater hope to patients and their families and carers. In this volume, Cambridge Prescribers Guide in Psychiatry, authors have brought together key essentials about medications used in treatments in psychiatry in an impressively coherent and comprehensive manner. The authors deserve our thanks and congratulations on an impressive effort to bring together evidence-based information on how to use medicine and drug interventions which will go a long way in improving outcomes for patients and their carers as well as families.”
Dinesh Bhugra, CBE Professor Emeritus, Mental Health & Cultural Diversity, IoPPN Kings College, London
“Finally, a colourful handbook about medication in use in psychiatry that you could look up quickly in the field like a bird-watcher guide. Modern clinical practice involves a reflective integration of psychopharmacology with psychosocial interventions that depend on a good grasp of the brain mechanism behind the medication used. Filtering and updating information is difficult for the busy clinician, who could find himself stuck in the clinic trying to google a less familiar medication or side effect. It is particularly reassuring to learn that The Cambridge Prescriber’s Guide in Psychiatry is the product of coordinated crowd-sourcing of clinical students, active clinicians, as well as neuroscience experts. In particular, the unique section on the Art of Psychopharmacology for each medication presents the wisdom of practising clinicians which has hitherto largely been confined to clinical supervision in specialist apprenticeships. This work will find its place in the pockets of busy clinicians and will be a reliable source of information for students, healthcare professionals, patients and carers.”
Professor Eric Chen MA(Oxon), MBChB(Edin), MD(Edin). FRCPsych(UK), FHKAM(Psychiatry)
The University of Hong Kong
“The Cambridge Prescriber’s Guide in Psychiatry will support informed and inclusive decisions about psychiatric medication as the basis of better outcomes for patients. The collaborative authorship combines Cambridgeshire & Peterborough’s experienced NHS consultants, psychopharmacologists and pharmacists with the inquiring minds of our student doctors: an innovative example of why it is so rewarding to practise psychiatry in an academic teaching trust environment. The Cambridge Prescriber’s Guide in Psychiatry will help make that inquisitive, evidence-based approach more widely available to prescribers in mental health care.”
Dr Cathy Walsh Chief Medical Officer
Cambridgeshire and Peterborough NHS Foundation Trust
“From Acamprosate to Zuclopenthixol - The Cambridge Prescriber’s Guide in Psychiatry is what it says on the tin. Crystal clear information that prescribers need – to not only prescribe safely and effectively in terms of dosing and side effects but also to understand the underlying mechanism of action. Neat colour coded sections with easy to access bullet point lists of key information makes the guide an easyto-use reference tool and psychopharmaco-pedia rolled in one. Sections on the art of switching and on the mechanism of action of side effects will be appreciated equally by established clinicians as by trainees across the world. The short but pertinent list of references at the end of each medication will also appeal to those with a more academic interest in psychopharmacology. The inclusion of compound medications (e.g. Buprenorphine and Naoloxone) in the guide is especially welcome lending credence to the title of the guide as a Prescriber’s guide. I particularly liked The Art of Psychopharmacology and Pearls sections, what I call the ‘Wisdom sections’. Overall, the various sections are guaranteed to make every medication choice discussion with the patient an intellectually stimulating encounter and one that should result in a more rational, more safe prescribing practice – win-win for both patients and prescribers.”
Subodh Dave Dean
Royal College of Psychiatrists
Cambridge Prescriber’s Guide in Psychiatry
Edited by Sepehr Hafizi
Cambridgeshire and Peterborough NHS Foundation Trust and University of Cambridge, Cambridge
Peter B. Jones
University of Cambridge, Cambridge
Stephen M. Stahl
University of California, San Diego
With illustrations by Nancy Muntner
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First published 2024
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Every effort has been made in preparing this book to provide accurate and up-to-date information that 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.
70
Foreword
With psychiatric conditions being so prevalent and the wide indications of many available medicines, most doctors need to be confident about psychotropic drugs, regardless of whether they prescribe them themselves. But tomorrow’s doctors walk a long road from the basic pharmacological principles they learn from the simplicity of the ileum to the complexities of the everyday lives of people seeking help for their mental health. The Cambridge Prescriber’s Guide in Psychiatry is intended to be an everyday reference to support the clinician, whether physician, psychiatrist or other medical or allied professional involved in helping those who require psychotropic drugs as part of their healthcare. The Guide maps the journey from basic pharmacology, through evidence-based prescribing to the “clinical pearls” section which is based on experience and expertise. I am delighted that students from the School of Clinical Medicine at the University of Cambridge have played a central role in compiling the Guide. They have sifted, compared and combined the many sources on which prescribers rely to create draft entries, drug-by-drug, to discuss with Associate Editors, mainly senior clinicians from the NHS organisations with which the Clinical School collaborates to provide psychiatric experience for the students. Thus, some of tomorrow’s doctors have not only greatly enhanced their learning experience in psychiatry but have contributed to today’s clinical practice. All will benefit in terms of their future practice and some, perhaps many, will find that their career path leads to psychiatry.
Professor Paul Wilkinson
Clinical Dean
University of Cambridge School of Clinical Medicine
Honorary Consultant in Child and Adolescent Psychiatry, CPFT
Acknowledgements
The Editors are grateful to the 34 students from the University of Cambridge and the Associate Editors who developed the draft entries with them, and to staff at CUP for their generous support during production.
Dr Hafizi acknowledges salary support from the NIHR Applied Research Collaboration East of England at the Cambridgeshire & Peterborough NHS Foundation Trust during the early stages of the project development through a Fellowship to enhance evidence-based practice. The views expressed are those of the Editors and not necessarily of the funder.
Introduction
The Cambridge Prescriber’s Guide in Psychiatry is intended to complement Stahl’s Essential Psychopharmacology, and the recently published Cambridge Textbook of Neuroscience for Psychiatrists. The former emphasises mechanisms of action and how psychotropic drugs work upon receptors and enzymes in the brain, while the Cambridge Textbook of Neuroscience for Psychiatrists reviews the wider understanding of neuroscience in psychiatry and its application to clinical practice. Thus, the Guide gives practical neuroscience-based information on how to use psychotropic drugs in clinical practice. We have used the tried, tested and popular format of Stahl’s Prescriber’s Guide, adapting it for a BritishEnglish readership and prescribers relying on a UK formulary.
We have taken the unusual step of involving tomorrow’s prescribers in the production of the Guide: student doctors at the School of Clinical Medicine, University of Cambridge. They reviewed the available pharmacological evidence and existing clinical guidelines according to templates and under the supervision of experienced consultants and pharmacists as Associate Editors; most of these Associate Editors are our clinical colleagues within the Cambridgeshire & Peterborough NHS Foundation Trust (CPFT). This information was then reviewed, cross-checked, and edited further. Through this inter-generational professional partnership, we hope to have excited the students’ interest in psychopharmacology and psychiatry while integrating the art of clinical practice with the science of psychopharmacology as seen through fresh eyes.
We cannot include all available information about every drug in a single work, and no attempt is made here to be comprehensive. The Guide comprises punchy information and essential facts to help prescribers in everyday practice. Unfortunately, it also means excluding less critical facts and arcane information that may, nevertheless, be useful to the reader. To include everything would make the book too long and dilute the most important information. In deciding what to include and what to omit, the editorial team has drawn upon common sense and many decades of combined clinical experience.
To meet the needs of the clinician and to facilitate future updates of the Guide, the opinions of readers are eagerly solicited. Feedback can be emailed to PrescribersGuide@ cambridge.org. Any and all suggestions and comments are welcomed.
As in Stahl’s Prescriber’s Guide, the selected drugs are all presented in the same format in order to facilitate rapid access to information. Specifically, each drug is broken down into five sections, each designated by a standard colour background: Therapeutics, Side Effects, Dosing and Use, Special Populations, The Art of Psychopharmacology, followed by Suggested Reading.
Therapeutics covers the brand names in the UK and if the generic form is available; the class of drug; what indications it is prescribed for as in the British National Formulary (BNF) in bold and other common non-BNF indications; how the drug works; how long it takes to work; what to do if it works or if it doesn’t work; the best augmenting combinations for partial response or treatment resistance; and the tests (if any) that are required.
Side effects explains how the drug causes side effects; gives a list of notable, lifethreatening or dangerous side effects; gives a specific rating for weight gain or sedation; and gives advice about how to handle side effects, including best augmenting agents for side effects.
Dosing and use gives the usual dosing range; dosage forms; how to dose and dosing tips; symptoms of overdose; long-term use; if habit forming, how to stop; pharmacokinetics; drug interactions; when not to use; and other warnings or precautions.
Special populations contains specific information about any possible renal, hepatic, and cardiac impairments, and any precautions to be taken for treating the elderly, children and adolescents, and pregnant and breast-feeding women.
The art of psychopharmacology provides the editorial team’s opinions on issues such as the potential advantages and disadvantages of any one drug, the primary target symptoms, and clinical pearls to get the best out of a drug for a specific patient.
The art of switching includes clinical pearls and graphical representations to help guide the switching process that can be particularly problematic unless the relevant pharmacological principles and profiles are considered.
The Medicines and Driving chapter outlines a summary of advice relating to driving for some of the individual drugs and classes of drugs found in the Guide.
There is a list of icons used in the Guide following this Introduction and at the back of the Guide are several indices. The first is an index by drug name, giving both generic names (uncapitalised) and trade names (capitalised and followed by the generic name in parentheses). The second is an index of common uses for the generic drugs included in the Guide and is organised by disorder/symptom. Agents that are approved in the BNF for a particular use are shown in bold but additional, evidence-based usage is also included. The third index is organised by drug class and lists all the agents that fall within each class. In addition to these indices there is a list of abbreviations.
We have attempted to make information consistent with what readers may see in other standard sources including the British National Formulary (BNF), British Association for Psychopharmacology condition-specific guidelines, Bumps (best use of medicine in pregnancy), Electronic Medicines Compendium, Martindale: The Complete Drug Reference, Maudsley Prescribing Guidelines, NICE Guidelines, Specialist Pharmacy Service, and The Renal Drug Handbook. Prescribers are encouraged to consult these standard references and comprehensive psychiatry and pharmacology textbooks for more in-depth information. They are also reminded that the Art of Psychopharmacology section is based on the Editors’ opinions.
It is strongly advised that readers familiarise themselves with the standard use of these drugs before attempting any of the less frequent uses discussed, such as unusual drug combinations and doses. Reading about both drugs before augmenting one with the other is also strongly recommended. Clinical psychopharmacologists, that includes all prescribers, should regularly track blood pressure, weight, and body mass index for most of their patients. The dutiful clinician will also check out the drug interactions of non-central nervous system (CNS) drugs with those that act in the CNS, including any prescribed by other clinicians with whom they should communicate. Initiating certain drugs may be for experts only. These might include clozapine and monoamine oxidase (MAO) inhibitors, among others. Off-label uses not included in the BNF, inadequately studied doses or combinations of drugs may also be for the expert only, who can weigh risks and benefits in the presence of sometimes vague and conflicting evidence. Pregnant or nursing women, or individuals with the features of two or more psychiatric illnesses, substance abuse, and/or a concomitant medical illness may be suitable patients for the expert. Controlled substances also require expertise. Use your best judgement as to your level of expertise: we are all learning in this rapidly
advancing field and all patients for whom we prescribe represent important n=1 trials from which we can enhance our knowledge.
The practice of medicine is often not so much a science as it is an art. It is important to stay within the standards of medical care for the field and within your personal comfort zone. We hope that the medical students involved in compiling the Guide will have learned as much about this art as they have done about the science of psychopharmacology; this art includes supporting patients to make informed decisions just as it does expertise in drug prescribing.
Finally, this book is intended to be genuinely helpful for practitioners of psychopharmacology by providing them with the mixture of facts and opinions selected by the Editors. Ultimately, prescribing choices are the reader’s responsibility. Every effort has been made in preparing this book to provide accurate and up-to-date information in accord with accepted standards and practice at the time of publication. Nevertheless, the psychopharmacology field is dynamic, and the Editors and publisher make no guarantees that the information contained herein is error-free. Furthermore, the Editors and publisher disclaim any responsibility for the continued currency of this information and disclaim all liability for any and all damages, including direct or consequential damages, resulting from the use of information contained in this book. Doctors recommending and patients using these drugs are strongly advised to consult and pay careful attention to information provided by the manufacturer.
List of icons
How the drug works, mechanism of action
Best augmenting agents to add for partial response or treatment resistance
Life-threatening or dangerous side effects
Weight Gain: Degrees of weight gain associated with the drug, with unusual signifying that weight gain has been reported but is not expected; not unusual signifying that weight gain occurs in a significant minority; common signifying that many experience weight gain and/or it can be significant in amount; and problematic signifying that weight gain occurs frequently, can be significant in amount, and may be a health problem in some patients
Sedation: Degrees of sedation associated with the drug, with unusual signifying that sedation has been reported but is not expected; not unusual signifying that sedation occurs in a significant minority; common signifying that many experience sedation and/or it can be significant in amount; and problematic signifying that sedation occurs frequently, can be significant in amount, and may be a health problem in some patients
Tips for dosing based on the clinical expertise of the author
Drug interactions that may occur
Warnings and precautions regarding use of the drug
Dosing and other information specific to children and adolescents
Information regarding use of the drug during pregnancy
Clinical pearls of information based on the clinical expertise of the author
The art of switching
Suggested reading
List of contributors
Associate Editors
Veronika Dobler StateExamMed, PhD, MRCPsych, PGDipCBT Consultant Child & Adolescent Psychiatrist, Cambridgeshire and Peterborough NHS Foundation Trust
Liliana Galindo MBBS, MRCPsych, Consultant Psychiatrist & Medical Leader in Psychosis, Cambridgeshire and Peterborough NHS Foundation Trust, University of Cambridge
George Griffiths MPharm, PgDip, Cambridgeshire and Peterborough NHS Foundation Trust
Neil Hunt MA, MD, MRCPsych, Consultant Psychiatrist, Cambridge, Affiliated Assistant Professor, University of Cambridge
Mohammad Malkera MBBS, MRCPsych, Consultant Psychiatrist, Liaison Psychiatry, CPFT; Affiliated Assistant Professor, University of Cambridge
Asha Praseedom MBBS, MRCPsych, Consultant Psychiatrist & Associate Clinical Director, Cambridgeshire and Peterborough NHS Foundation Trust
Pranathi Ramachandra MBBS, MRCPsych, Consultant Psychiatrist, Cambridgeshire and Peterborough NHS Foundation Trust
Judy Rubinsztein MBChB, FRCPsych, PhD (Cantab), PGCert MedEd, Affiliated Assistant Professor, University of Cambridge
Shamim Ruhi MBBS, MRCPsych, Consultant Psychiatrist, Norfolk and Suffolk NHS Foundation Trust
Contributors
At the time of writing all contributors were medical students at the University of Cambridge
• Maintenance of abstinence in alcoholdependence (moderate-severe condition in combination with psychosocial interventions)
How the Drug Works
• Theoretically reduces excitatory glutamate neurotransmission and increases gammaaminobutyric acid (GABA) to increase abstinence
• Binds to and blocks certain glutamate receptors, including metabotropic glutamate receptors
• Acts as a functional glutamatergic NMDA antagonist
• Because withdrawal of alcohol following chronic administration can lead to excessive glutamate activity and deficient GABA activity, acamprosate can act as “artificial alcohol” to mitigate these effects
How Long Until It Works
• Treatment duration of longer than 6 months suggested
• Has demonstrated efficacy in trials lasting between 13 and 52 weeks
If It Works
• Increases continuous/cumulative abstinence from alcohol
If It Doesn’t Work
• Evaluate for and address contributing factors
• Consider switching to another agent, e.g. naltrexone or disulfiram
• Consider augmenting with naltrexone
Acamprosate calcium
Best Augmenting Combos for Partial Response or Treatment
Resistance
• Naltrexone
• Augmenting therapy may be more effective than monotherapy
• Use in combination with individual psychological interventions (CBT, behavioural therapy, social network/ environment-based therapies)
Tests
• Baseline urea and electrolytes, liver function (including gamma-glutamyl transferase)
• Follow-up blood tests: liver function to check on recovery and to increase motivation
SIDE EFFECTS
How Drug Causes Side Effects
• Theoretically, behavioural side effects are due to changes in neurotransmitter concentrations at receptors in parts of the brain and body other than those that cause therapeutic actions
• Gastrointestinal side effects may be related to large doses of a drug that is an amino acid derivative, increasing osmotic absorption in the gastrointestinal tract
• Dose reduction or switching to another agent may be more effective since most side effects cannot be improved with an augmenting agent
DOSING AND USE
Usual Dosage Range
• Adult (body weight <60 kg): 666 mg in the morning, and 333 mg at midday and at night time
• Adult (body weight ≥ 60 kg): 666 mg 3 times per day
Dosage Forms
• Tablet 333 mg
How to Dose
✽ Maintenance of abstinence in alcohol dependence:
• Patients should begin treatment as soon as possible after achieving detoxification
• Some evidence suggests can be started during detoxification for neuroprotection
• Recommended dose is 666 mg 3 times daily, titration is not required
Dosing Tips
• Provide psychosocial intervention in combination with acamprosate treatment to increase the chances of success
• Stop if drinking persists 4 to 6 weeks after starting the drug
• Stay under supervision at least monthly for 6 months, then less frequently if taking more than 6 months
• Although absorption of acamprosate is not affected by food, it may aid adherence if patients who regularly eat three meals per day take each dose with a meal
• Adherence with the 3-times-daily dosing can be a problem; having patient focus on
frequent oral dosing of drug rather than frequent drinking may be helpful in some patients
Overdose
• Acute overdose can lead to persistent diarrhoea
Long-Term Use
• Should be prescribed for 6 months or longer (licensed for 1 year)
• Has been studied in trials for up to 1 year
Habit Forming
• No
How to Stop
• Taper not necessary
Pharmacokinetics
• Bioavailability reduced when taken with food
• Terminal half-life about 20–33 hours
• Excreted mostly unchanged via kidneys
Drug Interactions
• Does not inhibit hepatic enzymes, and this is unlikely to affect plasma concentrations of drugs metabolised by those enzymes
• Is not hepatically metabolised and thus is unlikely to be affected by drugs that induce or inhibit hepatic enzymes
• Concomitant administration with naltrexone may increase plasma levels of acamprosate but this does not appear to be clinically significant and dose adjustment is not recommended
Other Warnings/Precautions
• Monitor patients for emergence of depressed mood or suicidal ideation and behaviour (suicidality)
• Use cautiously in individuals with known psychiatric illness
• Continued alcohol abuse – risk of treatment failure
Do Not Use
• If the patient has severe renal impairment
• If the patient has severe hepatic impairment
• If there is a proven allergy to acamprosate
SPECIAL POPULATIONS
Renal Impairment
• For moderate impairment, recommended dose is 333 mg 3 times per day
• Contraindicated in severe impairment
Hepatic Impairment
• Dose adjustment not generally necessary
• Avoid in severe liver impairment
Cardiac Impairment
• Limited data available
Elderly
• Some patients may tolerate lower doses better
• Consider monitoring renal function
Children and Adolescents
• Safety and efficacy have not been established Pregnancy
• Controlled studies have not been conducted in pregnant women
• In animal studies, acamprosate demonstrated teratogenicity in doses approximately equal to the human dose (rat studies) and in doses about 3 times the human dose (rabbit studies)
• Pregnant women needing to stop drinking may consider behavioural therapy before pharmacotherapy
• Not generally recommended for use during pregnancy, especially during first trimester
• Alcohol is a confirmed teratogen and therefore acamprosate use during pregnancy may be considered beneficial in some cases
Breastfeeding
• No evidence of safety
• Long half-life increases the risk of accumulation in the breastfed infant
• Low levels anticipated in milk due to low oral absorption
• Benefit of the mother abstaining from alcohol to the infant may outweigh the risk to the infant of acamprosate
Acamprosate calcium
THE ART OF PSYCHOPHARMACOLOGY
Potential Advantages
• Individuals who have recently abstained from alcohol
• For the chronic, daily drinker
• It works as well as naltrexone for maintenance of abstinence from alcohol
Potential Disadvantages
• Individuals who are not abstinent at time of treatment initiation
• For binge drinkers
• Naltrexone works slightly better for reducing cravings for alcohol and heavy drinking
Primary Target Symptoms
• Alcohol dependence Pearls
• Because acamprosate serves as “artificial alcohol”, it may be less effective in situations in which the individual has not yet abstained from alcohol or suffers a relapse
• Thus, acamprosate may be a preferred treatment if the goal is complete abstinence but may not be preferred if the goal is reduced-risk drinking
• Studies have found that acamprosate works best when used in combination with psychosocial support since the drug facilitates a reduction in alcohol consumption as well as full abstinence
• Over 3 to 12 months it increases the number of people who do not drink at all and the number of days without alcohol
• It appears to work as well as naltrexone for maintenance of abstinence from alcohol, however, naltrexone works slightly better for reducing cravings for alcohol and heavy drinking
• Some evidence suggests that acamprosate is neuroprotective (it protects neurons from damage and death caused by the effects of alcohol withdrawal, and possibly other causes of neurotoxicity)
Acamprosate calcium (Continued)
Suggested Reading
De Witte P, Littleton J, Parot P, et al. Neuroprotective and abstinence-promoting effects of acamprosate: elucidating the mechanism of action. CNS Drugs 2005;19(6):517–37.
Kiefer F, Jahn H, Tarnaske T, et al. Comparing and combining naltrexone and acamprosate in relapse prevention of alcoholism: a double-blind, placebo-controlled study. Arch Gen Psychiatry 2003;60:92–9.
Kranzler HR, Soyka M. Diagnosis and pharmacotherapy of alcohol use disorder: a review. JAMA 2018;320(8):815–24.
Lingford-Hughes AR, Welch S, Peters L, et al. BAP updated guidelines: evidence-based guidelines for the pharmacological management of substance abuse, harmful use, addiction and comorbidity: recommendations from BAP. J Psychopharmacol 2012;26(7):899–952.
Maisel NC, Blodgett JC, Wilbourne PL, Humphreys K, Finney JW. Meta-analysis of naltrexone and acamprosate for treating alcohol use disorders: when are these medications most helpful? Addiction 2013;108(2):275–93.
Mann K, Kiefer F, Spanagel R, et al. Acamprosate: recent findings and future research directions. Alcohol Clin Exp Res 2008;32(7):1105–10.
Mason BJ, Heyser CJ. The neurobiology, clinical efficacy and safety of acamprosate in the treatment of alcohol dependence. Expert Opin Drug Saf 2010;9(1):177–88.
Nutt DJ. Doing it by numbers: a simple approach to reducing the harms of alcohol. J Psychopharmacol 2014;28(1):3–7.
Pilling S, Yesufu-Udechuku A, Taylor C, et al. Diagnosis, assessment, and management of harmful drinking and alcohol dependence: summary of NICE guidance. BMJ 2011;342:d700.
Plosker GL. Acamprosate: a review of its use in alcohol dependence. Drugs 2015;75(11):1255–68.
THERAPEUTICS
Brands
• Valdoxan
Generic?
Yes
Class
• Neuroscience-based nomenclature: pharmacology domain – melatonin, serotonin; mode of action – agonist and antagonist
• Agonist at melatonin 1 and melatonin 2 receptors
• Antagonist at 5HT2B and 5HT2C receptors
Commonly Prescribed for (bold for BNF indication)
• Major depression
• Generalised anxiety disorder
How the Drug Works
• Actions at both melatonin and 5HT2C receptors may be synergistic and increase noradrenaline and dopamine neurotransmission in the prefrontal cortex; may resynchronise circadian rhythms that are disturbed in depression
• No influence on extracellular levels of serotonin
How Long Until It Works
• Daytime functioning, anhedonia, and sleep can improve from the first week of treatment
• Onset of full therapeutic actions in depression is usually not immediate, but often delayed 2–4 weeks
• May continue to work for many years to prevent relapse of symptoms
If It Works
• The goal of treatment is complete remission of current symptoms as well as prevention of future relapses
• Treatment most often reduces or even eliminates symptoms, but is not a cure since symptoms can recur after medicine is stopped
• Continue treatment until all symptoms are gone (remission)
• Once symptoms are gone, continue treating for at least 6–9 months for the first episode
of depression or >12 months if relapse indicators present
• If >5 episodes and/or 2 episodes in the last few years then need to continue for at least 2 years or indefinitely
If It Doesn’t Work
• Many patients have only a partial response where some symptoms are improved but others persist (especially insomnia, fatigue, and problems concentrating)
• Other patients may be non-responders, sometimes called treatment-resistant or treatment-refractory
• Consider increasing dose as early as 2 weeks after initiating treatment if response is insufficient (decision on dose increase has to be balanced with a higher risk of transaminase elevation; dose increases should be made on an individual patient benefit/risk basis and with mandated liver function tests monitoring)
• Consider switching to another agent or adding an appropriate augmenting agent
• Consider psychotherapy
• Consider diagnosis or whether there is a co-morbid condition (e.g. medical illness, substance abuse, etc.)
• Some patients may experience lack of consistent efficacy due to the diagnosis actually being of a bipolar disorder, and require antidepressant discontinuation and consideration of a mood stabiliser or bipolar depression treatment
Best Augmenting Combos for Partial Response or Treatment Resistance
• SSRIs (excluding fluvoxamine), SNRIs, bupropion (use combinations of antidepressants with caution as this may activate bipolar disorder and suicidal ideation or agitation)
• Mood stabilisers or atypical antipsychotics for bipolar depression, psychotic depression, or treatment-resistant depression
• Modafinil, especially for fatigue, sleepiness, and lack of concentration
• Benzodiazepines
Tests
• Liver function tests before initiation of treatment and then at 3, 6, 12, and 24
weeks, and thereafter when clinically indicated
• When increasing the dose, liver function tests should be performed at the same frequency as when initiating treatment
• Liver function tests should be repeated within 48 hours in any patient who develops raised transaminases
SIDE EFFECTS
How Drug Causes Side Effects
• Adverse reactions usually mild to moderate and occur within the first 2 weeks of treatment
• Actions at melatonin receptors and at 5HT2C receptors could contribute to the side effects described below
• Rare activation of suicidal ideation and behaviour (suicidality) (short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo beyond age 25)
Weight Gain
• Occurs in significant minority
• In clinical studies, weight changes were similar to those in placebo
• Cases of weight decrease have been reported
Sedation
• Somnolescence occurs in significant minority
• Generally transient
• May be more likely to cause fatigue than sedation
What to Do About Side Effects
• Wait (unless related to liver)
• Wait
• Stop if transaminase levels reach 3 times the upper limit of normal
• Switch to another drug
Best Augmenting Agents for Side Effects
• Often best to try another antidepressant monotherapy prior to resorting to augmentation strategies to treat side effects
• Many side effects are time-dependent (i.e. they start immediately upon dosing and upon each dose increase, but go away with time)
• Many side effects cannot be improved with an augmenting agent
• Theoretically activation and agitation may represent the induction of a bipolar state, especially a mixed dysphoric state sometimes associated with suicidal ideation, and require the addition of lithium, a mood stabiliser or an atypical antipsychotic, and/or discontinuation of agomelatine
DOSING AND USE
Usual Dosage Range
• Major depression: 25–50 mg/day at bedtime
Dosage Forms
• Tablet 25 mg
How to Dose
• Major depression: initial dose 25 mg/day at bedtime; after 2 weeks can increase to 50 mg/day at bedtime
Dosing Tips
• If intolerable anxiety, insomnia, agitation, akathisia, or activation occur either upon dosing initiation or discontinuation,
consider the possibility of activated bipolar disorder and switch to a mood stabiliser or an atypical antipsychotic
Overdose
• Drowsiness and stomach pain, fatigue, agitation, anxiety, tension, dizziness, cyanosis, or malaise have been reported
Long-Term
Use
• Treatment up to 12 months has been found to decrease rate of relapse
Habit Forming
• No How to Stop
• No need to taper dose
Pharmacokinetics
• Oral bioavailability generally higher in women versus men
• Half-life 1–2 hours
• Metabolised primarily by CYP450 1A2 –dose adjustments may thus be necessary if smoking status changes
Drug Interactions
• Use of agomelatine with potent CYP450 1A2 inhibitors (e.g. fluvoxamine) is contraindicated
• Liver metabolism of agomelatine is induced by smoking
• Tramadol increases the risk of seizures in patients taking an antidepressant (class warning)
Other Warnings/Precautions
• Use with caution in patients with hepatic injury risk factors, such as obesity/ overweight/non-alcoholic fatty liver disease, diabetes, patients who drink large quantities of alcohol and/or have alcohol use disorder, or who take medication associated with risk of hepatic injury. Doctors should ask their patients if they have ever had liver problems
• Patients should be informed to seek immediate medical review if they experience symptoms related to liver disorder such as abdominal pain, bruising, dark urine, fatigue, jaundice, light-coloured stools, or pruritus
• Patients should be given a booklet with more information on the risk of hepatic side effects
Agomelatine
• Use caution in patients with pre-treatment elevated transaminases (> the upper limit of the normal range and < 3 times the upper limit of the normal range)
• Discontinue treatment if serum transaminases increase to 3 times the upper limit of normal; liver function tests should be performed regularly until serum transaminases return to normal
• Use with caution in patients with bipolar disorder or presenting in a hypomanic or manic state unless treated with concomitant mood-stabilising agent
• Warn patients and their caregivers about the possibility of activating side effects and advise them to report such symptoms immediately
• Monitor patients for activation of suicidal ideation, especially those below the age of 25
Do Not Use
• If patient has hepatic impairment
• If patient has transaminase levels > 3 times the upper limit of normal
• If patient is taking a potent CYP450 1A2 inhibitor (e.g. fluvoxamine, ciprofloxacin)
• If patient is taking MAO inhibitor (MAOI)
• If patient has galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption
• If patient has dementia
• If patient is over 75 years of age
• If there is a proven allergy to agomelatine
SPECIAL POPULATIONS
Renal Impairment
• Drug should be used with caution in moderate to severe impairment
Hepatic Impairment
• Avoid in hepatic impairment or if transaminases exceed 3 times the upper limit of normal
Cardiac Impairment
• Dose adjustment not necessary
Elderly
• Efficacy and safety have been established (< 75 years old)
• Dose adjustment not necessary
• Should not be used in patients aged 75 years and older
• Should not be used in elderly patients with dementia
Children and Adolescents
• Safety and efficacy have not been established and not recommended
Pregnancy
• Controlled studies have not been conducted in pregnant women
• Not generally recommended for use during pregnancy, especially during first trimester
• Must weigh the risk of treatment (first trimester foetal development, third trimester newborn delivery) to the child against the risk of no treatment (recurrence of depression, maternal health, infant bonding) to the mother and child
• For many patients this may mean continuing treatment during pregnancy
Breastfeeding
• Low levels anticipated in milk
• Extremely limited evidence of safety
• Monitor the infant for drowsiness, feeding difficulties and behavioural effects
• Immediate postpartum period is a high-risk time for depression, especially in women who have had prior depressive episodes, antidepressants may need to be reinstituted late in the third trimester or shortly after childbirth to prevent a recurrence during the postpartum period
• Must weigh benefits of breastfeeding with risks and benefits of antidepressant treatment versus nontreatment to both the infant and the mother
• For many patients this may mean continuing treatment during breastfeeding
• Other antidepressants may be preferable, e.g. paroxetine, sertraline, imipramine, or nortriptyline
Suggested Reading
THE
ART OF PSYCHOPHARMACOLOGY
Potential Advantages
• Patients with lack of energy, anhedonia, anxious co-morbidity, and sleep-wake disturbances
• Patients particularly concerned about sexual side effects or weight gain
Potential Disadvantages
• Patients with hepatic impairment
Primary Target Symptoms
• Depressed mood, anhedonia
• Functioning
• Anxiety with depression Pearls
• Agomelatine tends to be a third-choice antidepressant. It represents a novel approach to depression through a novel pharmacologic profile, agonist at melatonin MT1/MT2 receptors and antagonist at 5HT2C receptors acting synergistically
• This synergy provides agomelatine with a distinctive efficacy profile, different from conventional antidepressants with potentially an early and continuous improvement over time
• Agomelatine improves anhedonia early in treatment
• Improves anxiety in major depressive disorder
• May be fewer withdrawals/discontinuations for adverse events than with other antidepressants
• No significant effect on cardiac parameters such as blood pressure and heart rate
• Some data suggest that agomelatine may be especially efficacious in achieving functional remission
• Agomelatine may improve sleep quality by promoting proper maintenance of circadian rhythms underlying a normal sleep-wake cycle
Carvalho AF, Sharma MS, Brunoni AR, et al. The safety, tolerability and risks associated with the use of newer generation antidepressant drugs: a critical review of the literature. Psycother Psychosom 2016;85(5):270–88.
Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet 2018;391(10128):1357–66.
Agomelatine
DeBodinat C, Guardiola-Lemaitre B, Mocaer E, et al. Agomelatine, the first melatonergic antidepressant: discovery, characterization, and development. Nat Rev Drug Discov 2010;9:628–42.
Goodwin GM, Emsley R, Rembry S, Rouillon F. Agomelatine prevents relapse in patients with major depressive disorder without evidence of a discontinuation syndrome: a 24-week randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2009;70:1128–37.
Kennedy SH, Avedisova A, Belai’di C, et al. Sustained efficacy of agomelatine 10 mg, 25 mg, and 25–50 mg on depressive symptoms and functional outcomes in patients with major depressive disorder. A placebo-controlled study over 6 months. Neuropsychopharmacol 2016;26(2):378–89.
Stahl SM. Mechanism of action of agomelatine: a novel antidepressant exploiting synergy between monoaminergic and melatonergic properties. CNS Spectrums 2014;19:207–12.
Stahl SM, Fava M, Trivedi M, et al. Agomelatine in the treatment of major depressive disorder. An 8 week, multicenter, randomized, placebo-controlled trial. J Clin Psychiatry 2010;71(5):616–26.
Stein DJ, Picarel-Blanchot F, Kennedy SH. Efficacy of the novel antidepressant agomelatine on anxiety symptoms in major depression. Hum Psychopharmacol 2013;28(2):151–9.
Taylor D, Sparshatt A, Varma S, et al. Antidepressant efficacy of agomelatine: meta-analysis of published and unpublished studies. BMJ 2014;348:g1888 (erratum in BMJ 2014;349:g2496).
