The Maudsley Prescribing Guidelines for Mental Health Conditions in Physical Illness E-Book

Siobhan Gee

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Serie: The Maudsley Prescribing Guidelines Series
• Sprache: Englisch

Seitenzahl: 398

Veröffentlichungsjahr: 2024

Beschreibung

Meet the challenges of mental health prescribing in the physically unwell with this essential guide

Treating mental health conditions in physically unwell patients presents unique challenges for clinicians and other practitioners. The efficacy and safety of psychotropic medications is established in physically healthy patients. In physically unwell people, psychotropics can have different outcomes and give rise to serious adverse effects that can complicate or worsen physical health conditions. Many clinicians face difficult decisions about prescribing for mental health conditions in such cases, and reliable information for them is scarce.

The Maudsley^® Prescribing Guidelines for Mental Health Conditions in Physical Illness meets this urgent need with a comprehensive guide to the safe and effective pharmacological management of mental illness in physically unwell patients. Covering a wide range of physical health conditions and comorbidities, the book makes evidence-based recommendations on pharmacological interventions. It’s an essential resource for any clinical practitioner looking to balance the physical and mental wellbeing of people with concurrent physical and mental health conditions.

The Maudsley^® Prescribing Guidelines for Mental Health Conditions in Physical Illness readers will also find:

• Prescribing recommendations for mental health conditions including depression, anxiety, psychosis and bipolar affective disorder
• Detailed discussion of the consequences for mental health prescribing in physical health conditions such as cardiac disease, diabetes, chronic obstructive pulmonary disease, and many more
• Treatment of complex and frequently encountered clinical scenarios such as restarting psychotropics after overdose and steroid-induced psychiatric conditions

The Maudsley^® Prescribing Guidelines for Mental Health Conditions in Physical Illness is an essential reference for all prescribers, clinical pharmacists and nurses who work with patients with comorbid mental and physical illnesses.

Leseprobe

Table of Contents

Cover

Table of Contents

Series Page

Title Page

Copyright Page

Preface

Acknowledgements

Abbreviations

Chapter 1: Cardiac Disease

INTRODUCTION

HEART FAILURE

CORONARY HEART DISEASE

HYPERTENSION

STROKE

ATRIAL FIBRILLATION

ANTICOAGULATION

ADHD MEDICATION IN ADULTS WITH CARDIAC DISEASE

DRUG–DRUG INTERACTIONS

SUMMARY OF RECOMMENDATIONS

References

Chapter 2: Chronic Obstructive Pulmonary Disorder

INTRODUCTION

ANTIDEPRESSANTS IN COPD

ANXIOLYTICS IN COPD

ANTIPSYCHOTICS IN COPD

ADDICTIONS AND SUBSTANCE USE

DRUG INTERACTIONS

PATIENT INFORMATION

References

Chapter 3: Depression in Inflammatory Bowel Disease

INTRODUCTION

CHOICE OF ANTIDEPRESSANT

References

Chapter 4: Critical Care

DISCONTINUING OR CONTINUING PRE‐EXISTING PSYCHIATRIC MEDICATION

AGITATION AND ANXIETY

SUMMARY

References

Chapter 5: Surgery

INTRODUCTION

ANTIDEPRESSANTS

ANTIPSYCHOTICS

MOOD STABILISERS

ANXIOLYTICS

ADHD MEDICINES

ANTIDEMENTIA MEDICINES

SUMMARY

References

Chapter 6: Dialysis

RENAL REPLACEMENT THERAPY

DEPRESSION

PSYCHOSIS

THE EFFECT OF DIALYSIS ON PSYCHOTROPICS

SUMMARY

References

Chapter 7: Delirium

INTRODUCTION

MANAGEMENT

CHOICE OF DRUG

PHARMACOLOGICAL PROPHYLAXIS

SUMMARY OF RECOMMENDATIONS

References

Chapter 8: End of Life Care

INTRODUCTION

ANTIDEPRESSANTS

ANTIPSYCHOTICS

MOOD STABILISERS

References

Chapter 9: Sickle Cell Disease

INTRODUCTION

ANTIDEPRESSANTS

ANTIPSYCHOTICS

MOOD STABILISERS

PRIAPISM

DRUG INTERACTIONS

References

Chapter 10: Corticosteroid‐induced Psychiatric Adverse Effects

INTRODUCTION

RISK FACTORS

TIME OF ONSET

MANAGEMENT

PROGNOSIS

PROPHYLAXIS

SUMMARY

References

Chapter 11: Glaucoma

GLAUCOMA AND SERIOUS MENTAL ILLNESS

ANTIDEPRESSANTS

ANTIPSYCHOTICS

MOOD STABILISERS

References

Chapter 12: Starting Psychiatric Medicines after Overdose

GENERAL PRINCIPLES

ANTIDEPRESSANTS

ANTIPSYCHOTICS

PRACTICAL ADVICE

THERAPEUTIC REFERENCE RANGES AND HALF‐LIVES

References

Chapter 13: Non‐oral Routes of Administration

ENTERAL FEEDING TUBES

ANTIDEPRESSANTS

ANTIPSYCHOTICS

MOOD STABILISERS

OTHER DRUGS

SUMMARY

References

Index

End User License Agreement

List of Tables

Chapter 1

Table 1.1 Antipsychotics in heart failure

Chapter 3

Table 3.1 Gastrointestinal side effects of antidepressants

Table 3.2 Antidepressant doses for neuropathic pain and depression

Table 3.3 Plasma concentration ranges

Chapter 4

Table 4.1 Drugs that increase intrasynaptic serotonin

Guide

Cover Page

Series Page

Title Page

Copyright Page

Preface

Acknowledgements

Abbreviations

Table of Contents

Begin Reading

Index

WILEY END USER LICENSE AGREEMENT

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THE MAUDSLEY® GUIDELINES

Other books in the Maudsley® Prescribing Guidelines series include:

The Maudsley® Prescribing Guidelines in Psychiatry, 14th EditionDavid M. Taylor, Thomas R. E. Barnes, Allan H. Young

The Maudsley® Practice Guidelines for Physical Health Conditions in PsychiatryDavid M. Taylor, Fiona Gaughran, Toby Pillinger

The Maudsley® Guidelines on Advanced Prescribing in PsychosisPaul Morrison, David M. Taylor, Phillip McGuire

The Maudsley® Deprescribing Guidelines: Antidepressants, Benzodiazepines, Gabapentinoids and Z‐drugsMark Horowitz, David M. Taylor

The Maudsley® Prescribing Guidelines for Mental Health Conditions in Physical Illness

Siobhan Gee, MPharm, PGDip, MRPharmS (consultant), PhD

Consultant Pharmacist and Deputy Director of Pharmacy, South London and the Maudsley NHS Foundation TrustHonorary Senior Lecturer, King’s College, London, UK

David M. Taylor, BSc, MSc, PhD, FFRPS, FRPharmS, FRCPEdin, FRCPsych(Hon)

Director of Pharmacy and Pathology, South London and Maudsley NHS Foundation TrustProfessor of Psychopharmacology, King's College, London, UK

This edition first published 2025© 2025 John Wiley & Sons Ltd

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The right of Siobhan Gee and David M. Taylor to be identified as the authors of this work has been asserted in accordance with law.

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Paperback ISBN: 9781394192403

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Preface

More than 40% of people diagnosed with a serious mental illness have at least one concurrent physical illness. Prescribing medicines to treat the psychiatric condition can be complex in these circumstances. The prescriber will need to consider both the potential for prescribed medication to adversely affect any physical health condition and the possibility of altered response because of the presence of physical illness. Choice of medication in the physically unwell patient can be further complicated by a host of other factors. Some patients, for example, cannot take medicines orally, some are at the end of life, some may be on renal replacement therapy, and so on.

The challenges of managing mental health medicines in patients with complex physical comorbidity are faced daily in liaison psychiatry (also known as consultative psychiatry or consultation‐liaison psychiatry). As the global population ages and the prevalence of psychiatric conditions continues to increase, these challenges are also increasingly faced by psychiatrists working in all specialisms, both acute and chronic, inpatient and outpatient. This book aims to help the clinician navigate these prescribing scenarios and to be of use not only to psychiatrists but general physicians too.

The importance of treating psychiatric conditions in people with physical illness cannot be overstated. There is no doubt that for every physical illness, the presence of mental ill health adversely affects both morbidity and mortality. We hope this book will not only enable the choice of safe and effective medication in physically unwell patients, but also engender confident prescribing for mental illness, even in the face of severe physical illness.

Siobhan Gee

David M. Taylor

July 2024

Acknowledgements

The following have contributed to the 1st edition of the Maudsley® Prescribing Guidelines for Mental Health Conditions in Physical Illness.

John Archer

Grainne D’Ancona

Mary‐Jane Docherty

Petrina Douglas‐Hall

Alexa Duff

Nicola Kalk

Cathrine McKenzie

Calum Moulton

Larissa Ryan

Mark Samaan

Esha Sharma

Clare Thomson

Jessica Webb

Hayley Wells

Particular thanks go to colleagues based within the Mind & Body Programme at King’s Health Partners who obtained funding from the Maudsley Charity in 2019 to facilitate the development of these guidelines. The work of the Mind & Body Programme continues at King’s Health Partners to provide integrated mental and physical healthcare that aims to improve care and outcomes for patients in South East London. For more information, please contact [email protected].

Abbreviations

ACE

angiotensin‐converting enzyme

ADHD

attention deficit hyperactivity disorder

APD

automated peritoneal dialysis

ARF

acute respiratory failure

ATP

adenosine triphosphate

BD

bis die (twice a day)

BMI

body mass index

BNP

B‐type natriuretic peptide

BP

blood pressure

cAMP

cyclic adenosine monophosphate

CAPD

continuous ambulatory peritoneal dialysis

CCV

central compartment volume

CHD

coronary heart disease

CNS

central nervous system

COPD

chronic obstructive pulmonary disorder

CRP

C‐reactive protein

CYP

cytochrome P

DSM‐5

Diagnostic and Statistical Manual

5

ECG

electrocardiogram

ECHO

echocardiogram

ECT

electroconvulsive therapy

ENRICHD

enhancing recovery in coronary heart disease

EPSE

extrapyramidal side effect

FBC

full blood count

FDA

Food and Drug Administration

GABA

gamma‐aminobutyric acid

GI

gastrointestinal

HDAC9

histone deacetylase 9

IBD

inflammatory bowel disease

ICS

inhaled corticosteroid

ICU

intensive care unit

IL

interleukin

IM

intramuscular

INR

international normalised ratio

IV

intravenous

LABA

long‐acting beta‐2 agonist

LAMA

long‐acting muscarinic antagonist

MAO

monoamine oxidase

MAOI

monoamine oxidase inhibitor

MDMA

3,4‐methylenedioxymethamphetamine

MI

myocardial infarction

MIND‐IT

myocardial infarction and depression intervention trial

MOOD‐HF

mood and mortality in depressed heart failure patients

NaCl

sodium chloride

NaSSA

noradrenaline and specific serotonergic antidepressant

NG

nasogastric

NHS

National Health Service

NICE

National Institute for Health and Care Excellence

NJ

nasojejunal

NMDA

N‐methyl‐d‐aspartate

NNT

number needed to treat

NOAC

non‐vitamin K antagonist oral anticoagulant

NRT

nicotine replacement therapy

NSAID

non‐steroidal anti‐inflammatory drug

NT‐pro BNP

N‐terminal pro B‐type natriuretic peptide

OD

omni die (once a day)

PEG

percutaneous endoscopic gastrostomy

QTc

QT interval adjusted for heart rate

RASS

Richmond Agitation Sedation Scale

RCT

randomised controlled trial

SABA

short‐acting beta‐2 agonist

SADHART‐CHF

sertraline against depression and heart disease in chronic heart failure

SAMA

short‐acting muscarinic antagonist

SC

subcutaneous

SIADH

syndrome of inappropriate antidiuretic hormone secretion

SL

sublingual

SMI

serious mental illness

SNRI

serotonin and noradrenaline reuptake inhibitor

SSRI

selective serotonin reuptake inhibitor

STAR*D

Sequenced Treatment Alternatives to Relieve Depression programme

TCA

tricyclic antidepressant

TDS

ter die sumendum (three times a day)

TNF

tumour necrosis factor

UC

ulcerative colitis

UK

United Kingdom

USA

United States of America

Vd

volume of distribution

Chapter 1Cardiac Disease

CONTENTS

Introduction

Heart failure

Depression and anxiety in heart failure

Psychosis and bipolar disorder in heart failure

Antidepressants

Antipsychotics

Clozapine

Mood stabilisers

Others

Coronary heart disease

Depression and anxiety in coronary heart disease

Psychosis and bipolar disorder in coronary heart disease

Antidepressants

Antipsychotics

Mood stabilisers

Others

Hypertension

Depression and anxiety in hypertension

Psychosis and bipolar disorder in hypertension

Antidepressants

Antipsychotics

Mood stabilisers

Others

Stroke

Depression, anxiety, and stroke

Psychosis, bipolar disorder, and stroke

Antidepressants

Antipsychotics

Mood stabilisers

Others

Atrial fibrillation

Depression, anxiety, and atrial fibrillation

Psychosis, bipolar disorder, and atrial fibrillation

Antidepressants

Antipsychotics

Mood stabilisers

Others

Anticoagulation

Antidepressants

Antipsychotics

Mood stabilisers

Others

ADHD medication in adults with cardiac disease

Summary

Recommendations

Drug–drug interactions

ACE inhibitors

Angiotensin‐II antagonists

Beta blockers

Calcium channel blockers

Sacubitril/valsartan

Spironolactone/eplerenone

Ivabradine

Digoxin

Hydralazine

Nitrates

Loop diuretics

Summary of recommendations

References

INTRODUCTION

The influence of psychiatric symptoms on the functioning of the heart was first described in 1628 by Sir William Harvey, the English physician who discovered the cardiac circulatory system. Since then, numerous studies have proven him correct, finding mental illness to be a significant predictor of cardiac mortality across the spectrum of cardiac diseases. Treatment of the mental illness is therefore vital not only for relief of psychiatric symptoms, but also for optimal treatment of the cardiac disease.

Few data are available to compare efficacy of drugs for mental illness within individual physical illnesses, such as heart failure or coronary heart disease, and even fewer for patients who have more than one concurrent physical illness. When extrapolating data from studies in patients without cardiac disease, it should be noted that populations studied in these trials are different (e.g. cardiac disease patients tend to be older than populations with general depression). Perhaps more importantly, the biological symptoms of mental illnesses that are measured by standard rating scales may not appear to improve on addition of psychiatric drugs because of the overlap of these physical symptoms with ongoing symptoms of the heart disease (e.g. fatigue, insomnia). Failure to demonstrate response to a drug on a rating scale is of little importance in clinical practice (symptoms are the target) but is relevant if trial data are used to make decisions about drug choice. Conversely, it is also possible that illnesses such as depression or anxiety – specifically in the context of heart disease – are biologically distinct from general depression. Consequently, drug treatments may not be effective for this reason.

HEART FAILURE

Depression and anxiety in heart failure

As many as one in five patients with heart failure suffer from depression, more than doubling the mortality risk and trebling the risk of non‐compliance with medical treatment recommendations1. Clinically significant symptoms of anxiety are also commonly reported in patients with heart failure (30%)2. Symptoms of heart failure and those of anxiety may overlap, increasing the apparent prevalence. A clear link between anxiety and mortality in heart failure has not been fully established, but an increased risk is evident for patients with other cardiac disorders such as coronary artery disease3. Of course, depression and anxiety may co‐exist, and together they increase the risk of both cardiac rehospitalisation and mortality in patients with heart failure4.

There are several factors that may give rise to the link between depression and anxiety, and poor cardiac outcomes in heart failure. These include biological changes that occur in association with the mental health condition (inflammation, autonomic dysfunction, alterations in the ability of platelets to aggregate, and endothelial dysfunction2). Adherence to medicines for the treatment of the heart failure or comorbidities may be affected, as may maintenance of a healthy lifestyle (smoking cessation, diet, exercise).

There are few data relating to the efficacy of pharmacotherapy in depression specifically with comorbid heart failure. The most well‐known studies are SADHART‐CHF (Sertraline Against Depression and Heart Disease in Chronic Heart Failure) and MOOD‐HF (Mood and Mortality in Depressed Heart Failure patients). SADHART‐CHF demonstrated safety (although not efficacy) of sertraline5, and MOOD‐HF6 the same for escitalopram. There are no randomised trials examining the pharmacological treatment of anxiety in heart failure patients.

Psychosis and bipolar disorder in heart failure

Patients with serious mental illness (SMI – schizophrenia, bipolar disorder, and severe depression) have a reduced life expectancy compared with the non‐SMI population7. Cardiovascular disease is a significant contributor to this8. Lifestyle interventions are as important in this population as they are in the general population9. Antipsychotics and mood stabilisers (lithium and mood‐stabilising antiepileptics) commonly cause weight gain, hyperglycaemia, and hyperlipidaemia. Despite this, patients who take them have an overall reduction in cardiac (and all‐cause) mortality10. This may be a direct beneficial effect of reduction in psychiatric symptoms, improved adherence to healthy lifestyle choices, and/or better compliance with physical health treatments. Heart failure outcomes in patients who have SMI are therefore strongly linked to the outcome of their mental illness, making effective treatment of the psychiatric symptoms a priority. This is an important factor when weighing the risks and benefits of individual psychiatric medication choice. Medication that is perceived as safer in heart failure but less effective for the mental disorder may not actually be the optimal choice for overall cardiac outcomes11.

Antidepressants

In general, SSRIs are considered first‐line antidepressants, and this is also true for patients with heart failure. Of the SSRIs, sertraline12,13 is generally well tolerated and efficacious in non‐heart failure populations14. It has few drug interactions, less propensity than citalopram to prolong the QTc, and has been studied in patients with heart failure (it is safe, but efficacy is unproven)5. Escitalopram has also demonstrated safety (although not efficacy) in patients with heart failure6, but is more often associated with QT prolongation15 than sertraline (although this association is disputed16).

Other options carry some cautions. Mirtazapine is consistently shown to promote appetite, probably due to α2 receptor blockade and affinity for H1, D1, and D2 receptors17, and is therefore less desirable in conditions such as heart failure where excess weight can be detrimental to clinical outcomes. Citalopram may be more likely than other antidepressants to prolong the QT interval and is not recommended for use in uncompensated heart failure18. SNRIs (venlafaxine and duloxetine) are associated with dose‐dependent increases in blood pressure19 (see section on hypertension), and venlafaxine and fluoxetine may also cause prolonged QT, particularly in combination with ivabradine20. Tricyclic antidepressants (TCAs) are generally avoided in patients with cardiac disease due to their effects on cardiac contractility, their proarrhythmic effects (due to blockade of cardiac sodium and potassium channels), and their potential to worsen ischaemic heart disease.

Hyponatraemia is a risk with all antidepressants in the first month of treatment. Depending on the patient’s risk profile, the diuretic dose may need to be adjusted. If hyponatraemia persists, the dose of sacubitril may need to be reduced or stopped. Mirtazapine and agomelatine may be less commonly associated with hyponatraemia (but are not completely without risk). Close monitoring of sodium levels is recommended, especially in the first few weeks of treatment21 and if patients have additional risk factors for developing hyponatraemia.

Recommendation: sertraline.

Antipsychotics

Most antipsychotics are associated to some degree with numerous cardiac adverse events, including prolonged QT interval, tachycardia and orthostatic hypotension. They can also (rarely) cause myocarditis and cardiomyopathy, which can lead to the development of heart failure. Pharmacovigilance studies suggest that myocarditis and cardiomyopathy may be particularly associated with chlorpromazine, fluphenazine, risperidone, and haloperidol (and clozapine; see below)22. Haloperidol, olanzapine, quetiapine, risperidone, and sulpiride have higher affinity than others for cardiac potassium channels and are associated with a higher risk of ventricular arrhythmia and sudden cardiac death23. Cariprazine, lurasidone, brexpiprazole, and lumateperone are considered safer choices in patients at risk of cardiac events, as they appear to exert minimal effects on the QT interval. They, along with ‘typical’ antipsychotics such as haloperidol, are also less likely than other ‘atypical’ drugs to cause weight gain and have adverse effects on blood lipids24. Olanzapine and clozapine are particularly problematic in this regard, and so may worsen the patient’s cardiovascular risk factor profile.

Where patients develop symptomatic heart failure that is suspected to be caused by antipsychotic‐induced cardiomyopathy, the offending drug should be changed to a different agent. For some patients this may be challenging if their psychiatric illness fails to respond to alternative antipsychotics. It has been suggested that a cut‐off of 45% ejection fraction be used as a threshold for treatment cessation, extrapolating from guidelines for monitoring of cardiotoxic chemotherapies25, but the exact level depends on the clinical scenario. After this point, studies indicate that the left ventricular function is less likely to recover25. Up to this threshold, effective antipsychotic treatments can be continued with 3‐monthly monitoring of heart failure symptoms and NT‐proBNP (a significant rise indicates raised cardiac filling pressures and should prompt an ECHO)26.

For patients with pre‐existing heart failure who require an antipsychotic, or need their current antipsychotic switched, choice of drug should primarily be focused on efficacy and tolerability. As described above, cariprazine, lurasidone, brexpiprazole, and lumateperone are preferable from a cardiac safety perspective. It is not known whether pre‐existing heart failure predisposes to drug‐induced cardiomyopathy, but it is the case that drug‐induced cardiomyopathy worsens heart failure. For this reason, monitoring for any unexpected deterioration in cardiac function on commencing a new antipsychotic in someone with heart failure is recommended. Continued vigilance is required as antipsychotics may cause cardiomyopathy after many months of treatment, and this monitoring is best managed in a multidisciplinary setting involving both the psychiatry and cardiology teams.

Recommendation: cariprazine, lurasidone, brexpiprazole, lumateperone. Avoid olanzapine.

Clozapine

Of the antipsychotics, clozapine is particularly associated with myocarditis and cardiomyopathy (although these are still rare events). Nonetheless, it is possible to start clozapine in patients with pre‐existing heart failure or continue clozapine if heart failure develops during treatment. In many cases this may be essential. Switching to a different antipsychotic when clozapine is indicated will almost inevitably result in psychiatric relapse. This can have dire consequences on the ability of the patient to comply with treatment for heart failure. Successful rechallenge with clozapine, even where cardiomyopathy is thought to be clozapine‐induced, is achievable27. The enhanced risk of drug‐induced cardiomyopathy with clozapine when compared with other antipsychotics means that monitoring cardiac function whilst establishing treatment is even more important. Use a slow titration of initial doses and monitor as described in Table 1.1.

Table 1.1 Antipsychotics in heart failure

Event

Action

Antipsychotic‐induced cardiomyopathy with symptoms of heart failure

Antipsychotic is effective.

Continue treatment if ejection fraction > 45%. Switch treatment if ejection fraction < 45%. Monitor symptoms and NT‐proBNP 3 monthly.

Antipsychotic is ineffective.

Switch, ideally to cariprazine, lurasidone, brexpiprazole, or lumateperone.

Non‐antipsychotic induced heart failure (new or pre‐existing)

Antipsychotic is effective.

Continue treatment.

Antipsychotic is ineffective.

Switch, ideally to cariprazine, lurasidone, brexpiprazole, or lumateperone.

Antipsychotic‐induced cardiomyopathy with ejection fraction < 45%. Offending antipsychotic has been stopped but alternative agents are ineffective.

Ensure optimisation of heart failure treatments before and during rechallenge. Ideally, wait until ejection fraction > 45%. Restart antipsychotic using a slow dose titration. Minimum weekly assessment of heart failure symptoms, HR, temp, trop, BNP, ECG

26

during dose titration (some authors suggest twice weekly troponin and CRP

28

). ECHO on completion of dose titration or earlier if indicated by symptoms or blood tests.

Mood stabilisers

Pharmacovigilance database studies have linked lithium to an increased risk of myocarditis and cardiomyopathy22, and case reports describe various cardiac adverse effects, including sinus node dysfunction, premature ventricular beats, atrioventricular block, and T‐wave depression. These risks must be balanced against the (probably unparalleled) efficacy of lithium in bipolar disorder. Carbamazepine may be associated with hypotension, bradycardia, atrioventricular block, and possibly heart failure29. Heart failure has also been reported with valproate30, and a Danish cohort study recently found an increased hazard ratio for mortality due to heart failure in elderly patients with epilepsy treated with valproate, compared with lamotrigine (or levetiracetam)31. The authors postulated that this association may be due to the effect on cardiac conduction by valproate blockade of voltage‐gated sodium channels, and possibly upregulation of anabolism of angiotensin II31. Other antiseizure drugs do not share this effect on angiotensin and may be safer.

In 2021, a warning that lamotrigine exhibits class 1B antiarrhythmic activity was added to the FDA product label. To date, no other regulatory authority has done the same. The warning is based on unpublished in vitro studies demonstrating that lamotrigine inhibits cardiac sodium channels, and may therefore slow ventricular condition, inducing arrhythmia. A study in healthy patients failed to find any such ECG changes, but it is possible that people with structural heart disease or myocardial ischaemia are at higher risk. Consequently, the FDA recommends avoiding lamotrigine in people who have cardiac conduction disorders, ventricular arrhythmias, or cardiac disease (including heart failure). The risk may be higher in people with elevated heart rates or who are taking other sodium channel blockers32.

Recommendation: no drug is without risk. Lamotrigine may be preferable.

Others

Pregabalin can cause peripheral oedema, and case reports have been published reporting an associated with exacerbation of heart failure29. It should be used with caution, depending on the clinical scenario. Promethazine is a phenothiazine derivative and may prolong the QT interval, but the likelihood of progression to torsade de pointes appears to be low33. Diphenhydramine has been linked to QT prolongation in case reports, but in the context of congenital abnormalities34 or overdose35.

Benzodiazepines may worsen outcomes in heart failure. In two studies examining the management of insomnia36 or anxiety37 in heart failure, use of benzodiazepines was associated with increased rehospitalisation for heart failure and cardiovascular death. It is possible that this is a result of reduced respiratory drive adversely affecting heart failure symptoms. Conversely, a cohort study with an average 8‐year follow‐up period found a reduction in mortality for patients with heart failure prescribed benzodiazepines38, perhaps reflecting the impact of improved management of mental health on heart failure outcomes. This is echoed by a multicentre Spanish study39, where use of benzodiazepines during acute exacerbations of heart failure was not associated with differences in mortality after 7 days, despite patients receiving benzodiazepines having more severe cardiac symptoms at baseline. The dose may be important. A large Taiwanese study40 found a reduction in cardiovascular mortality and hospitalisation for heart failure in patients receiving benzodiazepines post myocardial infarction, but only where small doses were used (up to 5mg diazepam, or equivalent). This benefit was lost at higher doses, possibly due to confounding by disease severity (higher doses implying higher levels of anxiety), or interference with cardiac rehabilitation.

Overall, it is clear that treatment of anxiety is important for cardiac outcomes, and benzodiazepines may be useful but should ideally be reserved for short‐term use, in line with more general guidance on management of anxiety disorders.

The cholinesterase inhibitors (donepezil, rivastigmine, galantamine) can have vagotonic effects on the heart rate (i.e. bradycardia), and some cases of QT interval prolongation have been reported. These events are uncommon41, and several studies show a protective effect of cholinesterase inhibitors on new‐onset heart failure42 or heart failure hospitalisation43. Memantine also appears to be safe in heart failure and may reduce hospitalisation44.

CORONARY HEART DISEASE

Depression and anxiety in coronary heart disease

Between 15% and 30% of patients with coronary heart disease (CHD) are diagnosed with depression, a prevalence two to three times higher than the general population45, and experts consider this to be an underestimation. Depression is a risk factor not only for the development of CHD but for cardiovascular morbidity and mortality in patients with established CHD46. Numerous mechanisms have been proposed to explain this relationship47, both biological (altered autonomic nervous system activity, increased catecholamine levels, increased inflammatory activity, endothelial dysfunction, and platelet dysfunction) and behavioural (sedentary behaviour, poor diet, smoking, low medication adherence). There are now several studies examining whether treating depression can improve outcomes in CHD. The largest of these, ENRICHD48, failed to find any reduction in cardiac events when sertraline was given to patients who had had a myocardial infarction. However, secondary analysis of this and other trials, including SADHART49,50 and MIND‐IT51, suggests that improvement in depression may positively affect overall survival in patients with CHD.

Similarly, anxiety symptoms are common in CHD52. Anxiety is also an independent risk factor for the development of CHD53, and for cardiac54 and all‐cause mortality55 in CHD, particularly when comorbid with depression55. Despite this, there are very few studies specifically examining treatment of anxiety disorders as a primary outcome. Where they do exist, only generalised anxiety disorder or health‐related anxiety are assessed (e.g. anxiety specifically around a cardiac intervention)56. Of note, anxiety disorders may share common symptoms with CHD, including tachycardia, shortness of breath, and chest pain.

Psychosis and bipolar disorder in coronary heart disease

A very large meta‐analysis that included more than 3 million patients with serious mental illness and over 100 million controls8 confirmed an increased risk of CHD for people with schizophrenia. There was no significant association between CHD and bipolar disorder in this analysis, but bipolar disorder has been significantly associated with cardiovascular disease in longitudinal studies, and with cardiovascular‐related death8. Some data suggest that of the SMI subtypes, bipolar disorder confers the highest 10‐year cardiovascular risk57. Various contributing factors are proposed, including accelerated atherosclerosis, endothelial dysfunction, and oxidative stress58. Despite the increased risk, patients with SMI are less likely to receive evidence‐based management of CHD, both in terms of diagnosis and treatment58.

Antidepressants

TCAs should be avoided in patients with CHD. Studies demonstrate negative cardiac outcomes for patients with CHD taking TCAs (increased heart rate, reduction in heart rate variability, and increased pulse59,60). The safety of SSRIs and mirtazapine post myocardial infarction (MI) has been demonstrated in several landmark studies5,48,61, and it has further been suggested that the inhibitory effect of SSRIs on platelet activation may actually protect against MI62. This potential benefit (studies thus far have been underpowered to confirm this claim5) must be balanced against the increased risk of bleeding and gastric ulceration63 when co‐prescribing serotonergic antidepressants with aspirin or other antiplatelet therapies. A patient‐centred approach is suggested – mirtazapine may be preferred over sertraline if the patient is felt to be at significant increased risk of bleeding, but balance this with the increased longer‐term risk of weight gain with mirtazapine. See section on anticoagulation.

Recommendation: sertraline, or mirtazapine if significant bleeding risk.

Antipsychotics

Whether antipsychotics increase the risk of CHD is not clear. Some meta‐analyses suggest an increased risk of MI for antipsychotic drug users64,65, others do not66,67. The heterogeneity and retrospective design of many of the published studies (making it difficult to control for confounding factors) may be contributing to the variation in results. When considering individual antipsychotic drug choice, several factors may be relevant. These include the likelihood of the antipsychotic to cause ventricular arrhythmia (a cause of sudden cardiac death), or to prolong the QT interval (increasing the risk of torsades de pointes, leading to sudden cardiac death). The effect of the antipsychotic on metabolic parameters is also important, as cholesterol and triglyceride concentrations, hypertension, and obesity are associated with increased risk of CHD68. One study suggested that D3 receptor antagonism may contribute to the development of MI, possibly because of effects on platelet aggregation, atherosclerosis, vascular remodelling, and intimal permeability69. The authors linked this to their observation that amisulpride, a drug with particularly high affinity for the D3 receptor, also had the highest risk of MI in their study. This finding requires replication.

Antipsychotics with no apparent effect on the QT interval are cariprazine, brexpiprazole, lurasidone, and lumateperone12, and these drugs also have more benign metabolic profiles than others24. They are therefore preferred in patients with CHD. Aripiprazole may be used if a depot is required (note that there is a possible association with QT interval prolongation12).

Recommendation: cariprazine, lurasidone, brexpiprazole, or lumateperone.

Mood stabilisers

Lithium can be used in CHD, with some data suggesting it may even slow the progression of atherosclerosis70 and reduce cardiovascular mortality71. It can cause ECG changes, but at therapeutic plasma concentrations these are usually clinically insignificant72 (but note that the manufacturers contraindicate lithium use in cardiac disorders with rhythm changes). Carbamazepine is an inducer of the hepatic cytochrome P450 enzyme system, which is involved in the synthesis of cholesterol. As a result, carbamazepine increases serum cholesterol73,74 and this may translate to an increased risk of MI75. Lamotrigine and valproate do not negatively affect cholesterol concentrations73. Valproate is particularly associated with weight gain73 but several studies show that use is associated with lower cholesterol concentrations, and possibly a corresponding reduction in the incidence of MI75‐77.

Recommendation: lithium, lamotrigine, or valproate (but monitor for metabolic syndrome).

Others

Pregabalin can cause significant weight gain but, similarly to valproate, does not seem to cause clinically significant changes in cholesterol78 or increase the risk of MI75. Most studies examining these clinical outcomes are conducted in people with epilepsy, which itself may be a risk factor for cardiovascular events79. Where studies do control for the indication for the antiepileptic drug, however, the associations appear to remain75.

The manufacturers of promethazine advise caution in patients with severe coronary artery disease, but the exact reason for this is not clear. As described above, promethazine may prolong the QT interval, but its torsadogenic potential is low33. Similarly, the use of diphenhydramine is cautioned by the manufacturers in cardiovascular disease, presumably due to effects on QT interval. Otherwise, antihistamines appear to be safe. Benzodiazepines are used in the management of acute coronary syndrome, and limited data suggest they improve cardiac mortality risk post MI when used in low or moderate doses40. This may be a result of better management of anxiety, rather than a direct effect of the drugs themselves. Higher doses have been associated with increased cardiac mortality80.

As described above, the cholinesterase inhibitors may prolong the QT interval, so caution is advised in patients who are newly post MI. Otherwise, along with memantine, they may be protective for cardiovascular outcomes in coronary heart disease81, possibly due to a reduction in myocardial revascularisation43,82,83. For older adults, particularly those at risk of a cardiac event, the importance of minimising the total anticholinergic burden of prescribed medication is becoming increasingly clear. A recent case‐case‐time‐control study found an association between anticholinergic burden and acute cardiovascular events, with greater burdens conferring higher risk84. Use a tool such as Medichec (medichec.com) to calculate anticholinergic burden and deprescribe or select drugs with a lower score where possible.

HYPERTENSION

Depression and anxiety in hypertension

A relationship between hypertension and depression has been discussed since as early as 1898, when blood pressure was noted to rise in patients with depression85. Since then, research has suggested that the relationship may be bidirectional. Depression is an independent risk factor for developing hypertension86, and the ‘vascular depression’ hypothesis proposes that cerebrovascular disease, for which hypertension is a risk factor, causes microvascular brain damage that may drive some depressive symptoms87. In contrast, studies in healthy populations show higher systolic blood pressure to be linked to a better mood and increased well‐being88. Recently, a large UK imaging study with a 10‐year follow‐up time confirmed these two apparently contradictory associations – higher systolic blood pressure is linked to fewer depressive symptoms, and a diagnosis of hypertension is associated with more depressive symptoms89. The authors suggest that there may be a shared mechanism between subjective experience, emotional processing and pain that involves regulatory baroreceptors.

Anxiety was predictive of incidence of hypertension in the Framingham Heart Study90, a finding also demonstrated in earlier studies91 and confirmed in meta‐analyses92. Further, patients with hypertension may be at heightened risk of developing anxiety, possibly a result of fear of the diagnosis93. It may be that sympathetic nervous system hyperactivity and cardiovascular oxidative stress contribute to the relationship94.

Psychosis and bipolar disorder in hypertension

Meta‐analysis suggests a prevalence for hypertension in schizophrenia of 39%95, but rates may be higher in some areas (58% in the USA48, 54% in England96). A higher risk of hypertension is also found in bipolar disorder97,98, and in both conditions, treatment of hypertension is poor98. The presence of metabolic disorder is clearly important, and antipsychotics add to this risk. Other factors may also be influential; a genetic link between cardiometabolic disease and bipolar disorder is suggested99, and inflammation and autonomic activity in psychosis may also be contributory100.

Antidepressants

Hypertension and depression may share some pathology – both may involve overactivation of the sympathetic nervous system. Blockade of noradrenergic receptors in the heart, as well as centrally, may further sensitise the heart to sympathetic activation, increasing cardiac output and blood pressure101. This may be further exacerbated by drugs that block noradrenaline receptors, such as TCAs and SNRIs. Indeed, TCAs (and MAOIs) are associated with a risk of hypertensive crisis, and noradrenergic drugs (venlafaxine, duloxetine) are associated with dose‐dependent increases in blood pressure102(although the effect for venlafaxine is not clinically significant at doses below 200mg/day, and even above this is only significant for about 5% of patients103). The anticholinergic effects of drugs such as TCAs may also contribute to increases in systolic blood pressure102. None is recommended for patients with pre‐existing hypertension.

SSRIs do not appear to affect blood pressure104 and are therefore preferable.

Recommendation: sertraline.

Antipsychotics

Antipsychotics may cause hypertension either acutely, via α2 adrenergic receptor antagonism, or chronically, due to weight gain. Olanzapine, risperidone, and particularly clozapine have higher affinity for α2‐adrenergic receptors than other antipsychotics12, making sharp rises in blood pressure on initiation of these drugs more likely, due to noradrenaline‐mediated vasoconstriction. Olanzapine and clozapine are associated with more weight gain than other antipsychotics24, which increases the risk of developing (or worsening) hypertension.

Recommendation: avoid olanzapine and risperidone.

Mood stabilisers

Hypertension has been rarely described in case reports with carbamazepine105 and valproate106,107, although causality is not certain. Lithium108 and lamotrigine are not associated with hypertension.

Recommendation: all mood stabilisers are likely to be safe.

Others

Pregabalin and promethazine109 are not associated with hypertension. The manufacturers of diphenhydramine caution against its use in hypertension when given parenterally, as large intravenous doses produce a strongly anticholinergic effect110, but this does not appear to be a significant problem when taken orally. Benzodiazepines have hypotensive effects111, possibly due to potentiation of the inhibitory effect of GABA and vasodilation112. Of the anticholinesterase inhibitors, rivastigmine has been rarely associated with hypertension in post‐marketing surveillance, and hypertension is commonly reported as an adverse effect with galantamine. Donepezil does not appear to cause problems with blood pressure. Hypertension is common with memantine (4.1% of patients compared with 2.8% taking placebo113).

STROKE

Depression, anxiety, and stroke

Post‐stroke depression is common, with a third of stroke survivors developing depression at some point after the event114. The frequency is highest in the first year, affecting one in three patients115. The South London Stroke Register found the cumulative incidence to be 55%116, positioning post‐stroke depression as the norm rather than the exception. Various reasons for this have been postulated, including (1) depression being a risk factor for stroke; (2) both depression and stroke having risk factors in common; (3) depression being a psychological reaction to stroke; (4) depression being secondary to other stroke outcomes, such as cognitive impairment; and (5) stroke having a direct pathophysiological effect on the brain116. Post‐stroke mood disorders are strictly defined by the Diagnostic and Statistical Manual 5 (DSM‐5) as mood disorders due to stroke, but the ability to definitively determine causality in clinical practice is lacking. Trials generally include symptoms of depression appearing at any time point post‐stroke and include patients who had pre‐existing depression diagnoses. The most consistent predictors of post‐stroke depression are physical disability, stroke severity, a history of depression, and cognitive impairment115. It is associated with poorer functional outcomes after stroke115.

Anxiety is also common post‐stroke, with about one in four patients affected117. Comorbid depression is common118. Evidence to support optimal treatment choice is sparse119, despite an association of severe post‐stroke anxiety with poor outcomes and quality of life120.

Psychosis, bipolar disorder, and stroke

Schizophrenia8,121 and bipolar disorder8,122,123 are associated with an increased risk of stroke, with SMI as a whole conferring a two‐fold increased risk122. This is likely to be a result of the increased cardiovascular comorbidity in SMI, including diabetes, hypertension, and hyperlipidaemia. Not only is there an increased likelihood of stroke but there is also increased mortality post‐stroke in both the short (30‐day) and long (5‐year) term122,124. This may be a consequence suboptimal clinical care. Studies done in various countries worldwide have shown that patients with schizophrenia are less likely to receive thrombolysis or carotid imaging, be screened for hyperlipidaemia, be prescribed antihypertensives or anticoagulants, achieve target lipid levels post‐stroke, or receive outpatient stroke care125‐129. In one study, this translated to mortality at 1‐year post‐stroke in patients over 70 years of 47%, compared with 35% for those without schizophrenia126.

Antidepressants

SSRIs and nortriptyline are widely recommended as the antidepressants of choice post‐stroke12. They may be associated with less dependence on carers post‐stroke, less disability, less neurological impairment, and less anxiety and depression, including in people without a diagnosis of depression130. Treatment with fluoxetine or nortriptyline has been shown to reduce long‐term mortality in comparison with placebo, including in patients who were not depressed at baseline131. This protective effect appears to remain even if antidepressants are only given for a short period following the stroke, suggesting that the mortality risk exceeds the duration of the depression131. SSRIs, however, are problematic to use in patients also taking anticoagulants (inevitable if the stroke was ischaemic) or at risk of bleeding for other reasons (those who suffered haemorrhagic stroke). Nortriptyline is more attractive in this regard. Mirtazapine and agomelatine largely avoid issues with bleeding, but data supporting use post‐stroke are entirely lacking for agomelatine and are conflicting for mirtazapine. One cohort study suggested an increased risk of a second stroke with mirtazapine, although this was in older adults, and the risk appears to reduce with time. This may reflect the fact that undertreated depression itself is a risk factor for stroke132. Other studies support the safety and efficacy of mirtazapine post‐stroke133,134.

Recommendation: nortriptyline or mirtazapine if bleeding is a concern, but monitor for weight gain with mirtazapine. Otherwise, SSRI.

Antipsychotics

The association of antipsychotics with a heightened risk of stroke in elderly patients with dementia is well described. What this means for younger patients without dementia, who are taking antipsychotics for other mental illnesses, is less clear. Few studies specifically address this question, and where they do exist they use heterogeneous outcomes (stroke incidence versus mortality from stroke, for example) and durations of follow‐up (weeks to years). The impact of changes in antipsychotic prescription type is not clearly accounted for, and confounding by indication is difficult to control. Where studies attempt to report risk of stroke by drug type, this is usually by ‘first‐generation’ versus ‘second‐generation’ drugs, and results are conflicting.

Some studies report different results depending on stroke type (one Taiwanese study found an increased risk of ischaemic stroke, but not haemorrhagic, with atypical drugs)135; others do not report the stroke subtypes separately136. Systematic review and meta‐analyses also draw different conclusions depending on their chosen inclusion criteria67,136. Overall, it seems possible that antipsychotics may increase the risk of stroke. Whether this is due to some direct, acutely mediated effect is not clear. It is certainly the case that antipsychotics increase the risk of obesity and insulin resistance, which in turn are risk factors for cardiovascular and cerebrovascular disease. They are also associated with an increased risk of venous thromboembolism. At the moment, there are insufficient data to support choosing one drug over another, but minimising weight gain is important.

Recommendation: no obvious optimal choice. Avoid weight gain.

Mood stabilisers

Animal models show a neuroprotective effect of lithium post‐stroke137, and a few small trials suggest this benefit may translate into humans138, although data are as yet very limited139. In terms of de novo stroke, lithium appears to confer either no extra risk140, or possibly a reduced risk141. Variation in the histone deacetylase 9 gene (HDAC9) has been identified as a cause of large artery stroke. Inhibiting the activity of the HDAC9 protein might therefore reduce the risk of stroke, and one drug that has this activity is sodium valproate. Data so far available suggest that this might be the case77,142 (but note one case‐crossover study finding an increased risk of haemorrhagic stroke with acute use of valproate in bipolar disorder140). Lamotrigine appears to be safe140,143. Carbamazepine is associated with a higher risk of stroke than the other mood‐stabilising antiepileptics77,140 and should be avoided.

Recommendation: lithium, valproate, lamotrigine.

Others

Pregabalin is widely used in the treatment of pain post‐stroke144, and as with lithium, animal studies suggest a role in brain recovery145. Similarly, promethazine may be anti‐inflammatory post‐stroke146. Diphenhydramine is not known to pose a problem in stroke.

Animal models show a neuroprotective effect for GABA receptor agonists such as benzodiazepines in cerebrovascular disease, but this does not appear to extend to improvement in outcomes for acute stroke in people147. Benzodiazepine use may in fact increase mortality post‐stroke148, and there may be a dose‐related increased risk of incident stroke149. This may be due in part to an increased risk of pneumonia for patients taking benzodiazepines150, oversedation increasing the need for intubation, or higher incidence of falls. However, there are many confounding factors, including the increased likelihood of benzodiazepine use, particularly in patients who have other predictors of mortality such as delirium, agitation, or anxiety post‐stroke, and so a direct causal association has been disputed151. Nonetheless, it is prudent to avoid use where possible and to minimise doses where not possible.

Acetylcholinesterase inhibitors may be protective for ischaemic stroke, possibly because of a protective effect on endothelial cells and anti‐inflammatory mediated reduction in atherosclerosis152. They may also improve cognitive and functional impairment post‐stroke153,154. Memantine may exert similar neuroprotective effects from stroke by inhibition of NMDA channels, reducing excitotoxic injury155. Not all studies examining the safety of acetylcholinesterase inhibitors control for concurrent use of antipsychotics, which are known to increase the risk of stroke in dementia. Other confounders are also important, including BMI and physical activity, hypertension, and smoking. These discrepancies in study design may explain the findings by some of an increased stroke risk in previous users of acetylcholinesterase inhibitors156. However, the consensus is that they, and memantine, are likely to be safe.

ATRIAL FIBRILLATION

Depression, anxiety, and atrial fibrillation

Depression increases the risk of developing atrial fibrillation157,158, and the prevalence of depression is higher in patients with atrial fibrillation than in the general population (8–38% vs 1–2%)157