Abstract
A patient receiving treatment for over a decade for a recurring depressive illness had become effectively bed-ridden by the time he was referred for further management. The simple step of adding mirtazapine to the venlafaxine he was already taking restored him swiftly to good mental health, and he remained well on this combination of antidepressants. Unfortunately, the months in which he was unable to function before he took combination antidepressants resulted in the collapse of his small business, his only source of income, and the loss of his accommodation. Having been a public figure, he ended up on social welfare benefits. Understandably, quite apart from his suffering, he wanted to know why this treatment had not been offered to him before these events unfolded: was this a happy ending, or a personal disaster? He therefore wrote a newspaper article about his experiences, and was inundated with emails from sufferers pleading for access to such treatment, and expressing their anger that such therapy had not been offered to them, or that they had been warned by psychiatrists they named that it was ineffective, or inappropriate, even though they continued to suffer.
The failure to achieve remission in a large number of patients with depression is repeatedly reported in the scientific literature. Logically, evidence-based treatments, both pharmacological and non-pharmacological, should be the initial approach to treating depression. The question remains however, as to what to do next. Re-analysis of the diagnosis, dealing with illness-inducing stresses and personal vulnerabilities, supplementation of antidepressants with proven augmenting agents, and ensuring that adequate duration and dosage of individual antidepressants are adhered to, are a standard part of our therapy. But we all treat patients in whom depression persists, despite these measures, and many refuse ECT, regarding it as a drastic intervention.
International treatment guidelines for psychiatrists take the approach that combination antidepressants are one of the options available to treat refractory depression. For example, the NICE 2009 Guideline states, ‘combining antidepressant drugs with different modes of action is increasingly used in clinical practice’. [1] The American Psychiatric Association Practice guideline for the treatment of patients with major depressive disorder states ‘the addition of a second non-MAOI antidepressant may be helpful, particularly for patients who have had a partial response to antidepressant monotherapy’ [2]. The 10th Edition of the Maudsley prescribing guidelines (2009) lists certain combinations of antidepressants as one of the options for treating refractory depression, in a table headed ‘Refractory depression – First choice: Commonly used treatments generally well supported by published literature’ [3]. The CANMAT (Canadian Network for Mood and Anxiety Treatments) guidelines describe certain combinations as having Level 2 evidence [4]. In Australia however, Therapeutic guidelines: psychotropic dispute these statements, stating, ‘There is little evidence supporting the use of combined antidepressants in treatment resistant depression, and there are significant concerns regarding the potential for serious drug interactions’ [5]. The international acceptance of the safety and possible usefulness of combination antidepressants is exemplified by the STAR*D trial [6] carried out in the USA some years ago, where combination antidepressants (such as that described previously) were an integral component of the trial, with no safety precautions being stipulated for patients in these arms of the trial. This trial, approved by the Department of Health, involved over 4000 patients being treated by multiple prestigious psychiatrists and academic centres. I suggest that many readers of this editorial, were they practising in such countries, would regard combination antidepressants as a standard option in cases of resistant depression.
Questions must arise as to why combination antidepressants remain such a source of controversy in Australia, much to the surprise, embarrassment and shock of international visiting specialists. Indeed, Australian doctors at meetings and conferences overseas, in countries where combination antidepressants are widely used, might pause to reflect, before simply repeating some of the unscientific statements propounded in this area, and out of keeping with international literature and practice. In contrast to the traditional public statements, a survey of over 1100 respondents [7] showed that 79% of Australian consultant psychiatrists had already used combination antidepressants; up until this survey, such practice was essentially a secret. Nevertheless, many pharmacists still repeatedly question patients and doctors about taking two antidepressants simultaneously, having been trained to believe this is bad practice.
Similarly, general practitioners continue to be confused by the conflicting advice they receive from psychiatrists, and remain baffled by reference sources such as their practice software. A GP was told by both a consultant psychiatrist and by her practice software that the combination of an SSRI and the antidepressant bupropion (indicated in Australia for smoking cessation) was dangerous. She was distressed to learn that this combination is widely used in the USA and Canada (including in the STAR*D Trial) and, commented that ‘this is not fair to me or my patients’.
The danger of combination antidepressants particularly relates to the possibility of the serotonin syndrome. Examination by the author of reports to the Adverse Drug Reactions Advisory Committee some time ago indicated that the vast majority of such events in Australia were due to an idiosyncratic reaction to individual agents used as monotherapy, or to the combination of tramadol with SSRIs. The secrecy surrounding combination antidepressant prescribing means it is not possible to calculate the frequency of such reactions, most of which are mild [8]. MAO inhibitors should usually be avoided in combination antidepressants.
An aspect of patient treatment perhaps not well understood by doctors is the legal precept that the choice of treatment, after being fully informed, is the patient's right. A doctor who withheld information about the possibility of therapeutic abortion, would be seen legally in the same light as a doctor who withheld information about a recognized form of psychiatric therapy. To make matters even more patient-focused, a legal opinion states that ‘Nonfeasance may be as culpable as misfeasance’, meaning that there is a particular obligation on specialists to know and operate at an advanced level. Indeed, a previous edition of the Maudsley prescribing guidelines stated, ‘Patients have the right to factually accurate information about medicines and prescribing choices…It is morally right to impart all relevant information to those prescribed medication. Being ‘economical with the truth” is unethical, likely to damage relationships and perhaps lead to litigation’ [9].
How many cases similar to Mr X exist in Australian medical practice? What defence is there to a claim for income compensation following failure by doctors to inform such patients about treatments the rest of the world regard as quite reasonable? While we would all wish for all of our patients to respond to high level, evidence-based medicine, and while we would all wish for complex trials testing the effectiveness and safety of various combination antidepressants, it is incumbent upon us to discuss with our patients the relative benefits and relative risks of the other treatment options that are now available. Informed and intelligent patients are often adamant they wish to accept the risk inherent in all medical treatments, and the potentially greater risk of combinations, rather than face the inexorable suffering, suicide risk, and career and relationship destruction caused by refractory depression. A large majority of psychiatrists believe information on combination antidepressants should be passed on to general practitioners, and increasingly educated patients are likely to demand and enforce their rights to similar treatment information.
In my view, it is time for psychiatrists in Australia to reconsider the practices of world-renowned colleagues operating in populations involving hundreds of millions of people, and learn from their vast experience, rather than simply being influenced by local conservative views, out of keeping with what the majority of psychiatrists actually do [7]. Our patients deserve to be given every treatment option when faced with the unique suffering and destruction wreaked in families and our economy by depression which has not fully remitted. Adding mirtazapine, bupropion, reboxetine or agomelatine to SSRIs seem safe treatments, which can transform the lives of our patients.
Please note that the old tradition of shooting the messenger is now considered to be in very bad taste, especially by the messenger!