title sub title MDD: Management and Choosing Between Antidepressants

EXPERT MONOGRAPH ISSUE 45

Introduction

Major Depressive Disorder (MDD) represents a devastating cause of personal and societal dysfunction. MDD is a global illness with epidemiological studies showing prevalence rates

between 5% and 10% and lifetime prevalence rates between

15% and 20%, making it one of the commonest, if not the most

common, mental health problem1. Most studies suggest that

incidence is spread across the lifespan, with rates twice as high in

women as in men apart from late life. Recurrence and chronicity

are common and add to the high prevalence.

Rates of 5-year relapse rise rapidly with each recurrence, reaching

around 80% after the third episode. Natural history data suggest

up to 20% of patients with MDD will remain symptomatic after two

years. Taken together these factors lead to a high level of burden

with MDD rated as the leading cause of disability measured as

Disability Adjusted Life Years Lost (DALYs) of all health conditions in

the most recent estimates from the Global Burden of Disease Study.2

Take Home Messages

į The lifetime prevalence rate of Major Depressive

Disorder (MDD) is 15-20%

į Prolonged duration of untreated illness is associated

with poorer outcomes including higher relapse rates

į Comorbidity with MDD is the rule rather than the

exception

į For severe MDD, antidepressant medication is the

preferred option

į Understanding the patient’s priorities for treatment

of their MDD is critical when deciding the most

appropriate antidepressant to prescribe

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This article discusses a practical, evidence-based approach to the management of Major Depressive Disorder as it is likely to present in the real world setting.

NOVEMBER 22, 2019

PROFESSOR MALCOLM HOPWOOD MD FRANZCP

Professor Malcolm Hopwood is the Ramsay Health Care Professor of Psychiatry, University of Melbourne,

based at the Albert Road Clinic (ARC) in Melbourne, Australia. At the ARC he is the Director of the

Professorial Psychiatry Unit, which specialises in the assessment and treatment of complex mood and

anxiety disorders. His research areas of interest include psychopharmacology and clinical aspects of mood

and anxiety disorders. He has also led research into psychiatric aspects of ABI and other neuropsychiatric

disorders. In 2015, he became President of the Royal Australian and New Zealand College of Psychiatrists.

title sub title

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Hormonal Contraception Trouble-shooting Part One: The Overweight Woman

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MDD: Management and Choosing Between Antidepressants

Diagnosis of MDD is generally made by identifying the presence of low mood and/or anhedonia together with a number of other symptoms such as disturbance of sleep, libido or appetite, lowered energy and motivation, anxiety, feelings of helplessness, hopelessness and guilt and suicidal ideation.

These symptoms should be present for most of the day each day for at least two weeks3.

In reality, many patients have had symptoms for a considerable length of time before presentation. Patients who have already had a number of episodes are more likely to recognise symptoms early and present sooner. Reducing the length of time the illness remains untreated is an important individual and public health priority. Mounting evidence shows that prolonged duration of untreated illness is associated with poorer outcomes including higher subsequent relapse rates.

As important as the diagnosis of MDD itself is the acknowledgement that comorbidity is the rule rather than the exception.

For mild to moderate MDD without psychotic or melancholic features, psychotherapies such as Cognitive Behaviour Therapy (CBT) and Interpersonal Therapy (IPT) as well as antidepressants

have top level evidence to support their use.

Commonest mental health comorbidities include anxiety disorders, substance use disorders and personality dysfunction. Less common comorbid disorders such as previously undiagnosed bipolar disorder are extremely important to identify.

MDD is also associated with a range of predisposing and perpetuating factors such as physical illness and psychosocial factors including relationship difficulties, social isolation, financial stress or trauma. Careful differentiation of these additional diagnoses and risk factors is vital to adequately assess and manage each case of MDD.

The principles of MDD management are well outlined in recent guidelines such as those from the Royal Australian and New Zealand College of Psychiatrists (RANZCP) Clinical Practice Guidelines for the Treatment of Mood Disorders4.

As implied above, good management of MDD must follow a nuanced assessment. Occasionally, this will lead to identification of issues such as an undiagnosed physical illness, severe pain, or current substance dependence that present with a depressive syndrome but require management of the primary underlying disorder. It is important to note that the presence of such morbidities does not automatically exclude the presence of MDD.

It is equally important to manage physical health well in the patient with MDD. There is clear evidence that MDD, along with bipolar disorder and schizophrenia, share an association with increased rates of physical illness and that those illnesses have poorer outcomes, including mortality. For all patients with MDD, appropriate discussion about the diagnosis of concurrent physical illness and education around the course of the illness, aetiology and treatment are a vital part of management. Where possible, remediation of lifestyle factors such as sleep disturbance also form an important first level of care.

For mild to moderate MDD without psychotic or melancholic features, psychotherapies such as Cognitive Behaviour Therapy (CBT) and Interpersonal Therapy (IPT) as well as antidepressants have top level evidence to support their use.

In practice, the choice between these therapies may be influenced by patient preference or past treatment response. It is worth noting that while there is strong evidence for the effectiveness of CBT and IPT, there is also a large body of evidence that has shown the efficacy of the therapeutic relationship within therapy is equally important in determining outcome.

Of course, the combination of evidence based psychotherapy and antidepressant medication is also frequently utilised and while this would appear logical as a strategy, there is little evidence that proves the combination has greater response rates than either alone. For severe MDD, antidepressant medication is usually the preferred option.

Treatments such as augmentation of antidepressants with atypical antipsychotics or lithium, Transcranial Magnetic Stimulation (TMS) or antidepressant combinations are not considered first line therapy. Electroconvulsive therapy (ECT) is similarly not usually utilised as first line therapy but may, very rarely, be so used in extreme life-threatening circumstances.

In Australia, the initial choice of treatment for MDD is usually the decision of the treating GP. To make this decision, a discussion between the patient and the GP will usually take place with the key focus being to obtain a shared set of goals. This is the best remedy to the extremely frequent problem of poor adherence to therapy.

There has been much discussion about whether the maximum number of sessions of therapy available under the Better Access scheme is adequate. However, the reality is that the mean number

of sessions an individual patient actually attends is around three to four. Further, antidepressant adherence data here and globally suggests that of all the individuals started on antidepressant medication, only about 50% are still picking up a script three months later.

While these findings can be understood in many ways, such short term treatment is inconsistent with all guideline recommendations for the treatment of MDD.

This poor adherence is undoubtedly likely to be associated with poorer outcomes, both for the current episode and potential relapses. The process of shared decision making is a potential antidote to this common problem5.

Shared decision making involves a number of steps including initial education to facilitate an informed discussion and an exchange of priorities in care.

Local evidence6 from an audit in general practice suggests that there is a common misalignment of priorities in antidepressant selection whereby the practitioner is more likely to focus on perceived efficacy for classical symptoms of MDD, whereas the patient’s concerns are more likely to be weighted to potential side effects. This should be considered along with international evidence that suggests patients often value the return of their normal emotions of pleasure and normal sadness over the disappearance of classical depressive symptoms. Put together, this would suggest that it is critical to gain an adequate understanding of the patient’s perspective in making any treatment recommendations, summarised in the maxim that the best treatment is the one the patient will want to take.

In terms of recommending an antidepressant medication, the GP is now faced with a large choice of over 20 registered compounds in Australia. There are challenges in trying to review all the current literature and evidence, a significant proportion of which was designed predominantly for registration purposes and is further limited by the highly selective criteria for study entry, making the generalisability of the research questionable.

In particular, many of the studies are not primarily powered to answer the key question confronting the GP: what are the relative risks and benefits for one active antidepressant treatment over another?

To assist in answering this question, Cipriani et al7 have recently published the largest network meta-analysis examining the comparative efficacy and tolerability of 21 antidepressants in the acute treatment of MDD.

The studies in this meta-analysis included the majority of the antidepressants currently registered for the treatment of MDD in Australia, including the most commonly prescribed ones.

This form of meta-analysis brings together all available trials of acute antidepressant treatment of MDD, relies on an assumption that the trials are broadly comparable and thus trials can be accumulated and viewed collectively. For example, if there are three trials of antidepressant A versus placebo, and two trials of antidepressant B versus placebo, these results can be combined to give us information about antidepressant A versus B. Questions may arise about this assumption and how well it applies across different countries of study or different times. For example, the trials conducted with tricyclic antidepressants over 40 years ago largely included subjects with severe MDD who were often hospitalised whereas contemporary trials often effectively exclude subjects with severe MDD. It is therefore appropriate to test heterogeneity of these trials statistically and exclude those that are significant outliers and such a process has been done in this meta-analysis.

In total, the primary network meta-analysis included 522 trials including 116,477 subjects. The agents were compared on efficacy judged by response rate (generally equating to 50% improvement in depressive symptoms) and acceptability. The latter was assessed by all-cause patient dropout rates during the trial, an approximation of what proportion of patients in real life will stop treatment due to side effects. The authors also conducted a secondary analysis, only including head-to-head comparison studies between two active antidepressant agents.

A minor criticism of the analysis could be the use of response rate rather than true remission as the endpoint for efficacy. There is clear evidence that true remission is the most desirable outcome but this concept has only more recently been recognised by researchers and is still not considered central in the registration process. Analysis for remission was in fact included in an appendix to the study.

In the primary analysis, the main conclusion in relation to efficacy was that all the available antidepressants were more efficacious than placebo in terms of response rate.

While this would not appear surprising, it is in one sense a validation of the trial process, noting that many agents fail to achieve registration because of lack of efficacy in such trials. The finding is also an important counterpoint to a frequent public questioning of the efficacy of antidepressants which leaves many patients uncertain.

It is noteworthy that this result does not state that any antidepressant will always work and patients need to be encouraged not to give up if the first agent is unsuccessful. The most efficacious agent based on this data was amitriptyline and the least, reboxetine, with others ranging in between.

By contrast, the tolerability data as measured by dropout rate showed only agomelatine and fluoxetine as associated with less drop outs than placebo. Tolerability data is often underestimated in importance but is clearly critical given the need for adherence

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MDD: Management and Choosing Between Antidepressants

if a medication is going to have a chance of being effective. All other antidepressants were associated with a higher drop out rate than placebo, with clomipramine associated with the highest relative dropout rate. Again, some of these results may not appear surprising but are interesting to consider as part of the shared decision making process.

Shared decision making involves a number of steps including initial education to facilitate

an informed discussion and an exchange of priorities in care.

When only head-to-head trials featuring two or more active antidepressants were considered, a slightly different picture emerged. A series of antidepressants showed superiority (agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine and vortioxetine) over other antidepressants studied. Of potentially equal significance, a second group were judged as less efficacious in this analysis (fluoxetine, fluvoxamine, reboxetine and trazodone). These were measured using odds ratios and reboxetine as a reference.

It is noteworthy that the total number of studies and subjects involved in this analysis was 194 studies and 34,196 patients. It is also interesting to consider how these findings fit with the experience of prescribers. It is probably true that prescribers form impressions very quickly based on a relatively small number of patients, often in difficult clinical situations.

According to findings from the STAR-D study,8 the response rate to the third antidepressant used in each episode may be at best around 15%. As most new antidepressants are often first used as third or later options, mathematically many patients would need to be treated by an individual prescriber to form a reliable impression relative to other available agents. When this has been taken into account, the picture in terms of tolerability is somewhat akin to that seen in the overall analysis, with agomelatine, citalopram, escitalopram, fluoxetine, sertraline and vortioxetine being the best tolerated agents and amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone and venlafaxine being associated with the highest dropout rates.

In summary, it is very clear that major depression is one of the biggest public health challenges facing us as a global community. Ongoing efforts to reduce stigma and improve accuracy in diagnosis should increase the proportion of those suffering the disorder who present for care. Once diagnosis is made, guidelines provide

clear direction about the full range of social, psychotherapeutic and biological treatments. However, better outcomes will only be achieved through a marked lift in adherence to all forms of therapy.

Central to achieving this is the process of shared decision making, incorporating patient preference and non-negotiables. Information such as that available in the recent meta-analysis by Cipriani et al7 may aid in a better-informed discussion both for and with patients about the choice of antidepressant medication. Ultimately a choice of treatment that involves the patient as an equal partner is a choice that is likely to lead to a better outcome.

Declaration

Professor Malcolm Hopwood was commissioned by Healthed for this article. The ideas, opinions and information presented are solely those of the author. The advertiser does not necessarily endorse or support the views expressed in this article. The author declares no significant competing financial, professional or personal interests that might influence this article.

References:

1. Bromet E1, Andrade LH, Hwang I, Sampson NA, Alonso J, de Girolamo G, et al. Cross-national epidemiology of DSM-IV major depressive episode. BMC Med. 2011 Jul 26; 9: 90. DOI: 10.1186/1741-7015-9-90

2. World Health Organization. Depression and Other Common Mental Disorders: Global Health Estimates. Geneva. World Health Organisation. 2017. 21 p. Available from: https://apps.who.int/iris/bitstream/handle/10665/254610/WHO-MSD-MER-2017.2-eng.pdf

3. American Psychiatric Association, DSM-5 Task Force. Diagnostic and statistical manual of mental disorders: DSM-5™. 5th ed. Arlington, VA, US: American Psychiatric Publishing, Inc. 2013. 947 p. DOI: 10.1176/appi.books.9780890425596

4. Malhi GS, Bassett D, Boyce P, Bryant R, Fitzgerald PB, Fritz K, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Aust N Z J Psychiatry. 2015 Dec; 49(12): 1087-206. DOI: 10.1177/0004867415617657

5. Hopwood M. The Shared Decision-Making Process in the Pharmacological Management of Depression. Patient. 2019 Sep 23. DOI: 10.1007/s40271-019-00383-w. [Epub ahead of print]

6. TAILOR audit. Results held https://thinkgp.com.au/education/clinical-audit-tailor-target-antidepressant-initiation-choice-unlock-positive-patient (accessed 10/01/2018)

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7. Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y. 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 Apr 7; 391(10128): 1357-66. DOI: 10.1016/S0140-6736(17)32802-7. Epub 2018 Feb 21.

8. Rush AJ1, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006 Nov; 163(11): 1905-17. DOI: 10.1176/ajp.2006.163.11.1905

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Editorial TeamMedical Editors: Dr Linda Calabresi, Dr Vivienne Miller Managing Editor: Neil Harris Production Editor: Amanda Bryan Editorial Assistant: Sai Machiraju Executive Editor: Dr Ramesh Manocha