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Abstract

Aim: Less than half of those suffering major depressive episodes achieve remission with the first antidepressant provided and one-third of all patients suffering depression have a chronic condition. Clinical experience indicates that a substantial proportion of patients suffer treatment-resistant depression (TRD). Our aim is to explore the literature reporting the drug treatment of TRD, and to present such information as would be of interest to clinical psychiatrists.

Method: Literature searches were conducted using PubMed and entering the words antidepressant, augmentation, combined antidepressants, treatment resistant depression and the names of individual antidepressant medications.

Results: Most authors recommended that TRD should be first approached by reassessing the diagnosis, adding psychotherapy and attending to psychosocial factors. Details of the following pharmacological options were identified: (i) augmentation of the currently employed antidepressant with a medication which is not an antidepressant; (ii) change of antidepressant; and (iii) addition of a second antidepressant to the current antidepressant, or commencement of a combination of two antidepressants.

Conclusions: When monotherapy provided at the maximum manufacturer-recommended doses for 3–4 weeks has failed to provide remission in depression, the diagnosis should be confirmed, psychotherapy added and psychosocial factors should receive attention. In the sustained absence of remission, a better outcome may be obtained by augmenting the antidepressant, changing from a single-action to a double- or multiple-action drug, or by combining antidepressants.

Keywords

antidepressants combined antidepressants depression treatment resistant depression

Treatment resistant depression [TRD] was defined in 1974 as depression, which fails to respond to a standard course of antidepressants [1]. While the concept of TRD has been embraced, no definition has been universally accepted, and by 2003, at least 15 different definitions were available [2]. Thase and Rush [3] proposed a continuum of five stages of resistance, beginning at stage I, which is failure to respond to one adequate trial of a single agent, through to stage V, which is failure to respond to multiple classes of antidepressants and bilateral electroconvulsive therapy. This continuum incorporated a variety of definitions and is valuable for research purposes, but has less routine clinical utility. For the purposes of this paper we misquote Humpty-Dumpty to Alice: ‘When we use TRD, it means just what the authors we are citing chose it to mean’. In general terms we are referring to depression which has been treated with antidepressant medication at the maximum manufacturer-recommended dose for 3–4 weeks with at least one, but usually more, different agents sequentially.

‘It is not a useful concept if it is viewed simply as an uncritical mandate for ever more somatic therapies’ [4]. Since this caution was published in 1994, the importance of taking a fresh look and confirming the diagnosis, determining the subtype of depression, identifying comorbidity so as to tailor treatment and giving attention to psychosocial matters through family or individual psychotherapy, have been well established in depression management [5], [6] and need not be repeated in this paper.

It is relevant, however, that TRD may be of either melancholic or non-melancholic form [4], and that the clinical heterogeneity of TRD does not permit classification as a unique subtype of depression [2]. It may also be relevant that in the best designed studies, comorbid medical illness, anxiety and personality disorder have the least effect on treatment outcomes, and that the presence of these complications should not be seen as impediments to treatment [7], [8].

Bipolar depression appears unresponsive to antidepressants [9] and as bipolar spectrum conditions may have a prevalence of 5.5% in the general population [10], this diagnosis deserves special mention when considering TRD. The addition of a mood stabilizer to various antidepressants [11] and the addition of olanzapine to selective serotonin reuptake inhibitors (SSRIs) [12–14] appear to provide benefits. These augmentations are discussed later. Lamotrigine alone may have a place; further studies are necessary. For reviews see Keck and McElroy [15] and Malhi et al. [16].

A patient who fails to respond to one type of antidepressant may obtain remission with another. This suggests that biological heterogeneity may underlie at least some cases of TRD. The molecular basis of depression is poorly understood. It is reasonable to suppose that vulnerability to clinical depression may result from a variety, rather than one single, molecular aberration. Further, it is reasonable to suppose that such vulnerability may, at least in some instances, result from several molecular aberrations occurring simultaneously.

Chronic depression comprises 30–35% of all cases of depression [17], [18] and encompasses chronic major depressive disorder, dysthymic disorder, dysthymic disorder plus depressive disorder, and major depression in incomplete remission. Approximately 50% of patients diagnosed with major depressive disorder will experience a recurrent or chronic course for which long-term treatment is recommended [19]. An unknown proportion of the chronic depression population will meet criteria for TRD.

Remission is defined as the complete absence of symptoms (the patient no longer meets syndromal criteria for the disorder and has no more than minimal symptoms) [20]. This implies the restoration of occupational and psychosocial function. Remission has been quantified as the achievement of a Hamilton Rating Scale for Depression (HDRS) score of less than 7, or a Montgomery-Asberg Depression Rating Scale (MADRS) score of less than 8 [21]. Response has been quantified as reduction of at least 50% of the baseline HDRS or MADRS. However, remission has become accepted as the goal of treatment [22], [23].

Thase et al. [24] examined the results of eight randomised, double-blind studies of major depression in which antidepressants had been provided in adequate doses for 6 or 8 weeks. They found that SSRIs produced remission in only 35% of cases, while venlafaxine, a serotonin noradrenaline reuptake inhibitor (SNRI) produced a slightly better outcome, however, remission rate was still low at 45% of cases.

Response has been defined as an improvement ‘of sufficient magnitude… that the individual is no longer fully symptomatic’ (no longer meets syndromal criteria for the disorder) but continues to have evidence of symptoms [20]. It is widely quantified as a reduction of at least 50% of the baseline HDRS or MADRS scores [25]. When current antidepressants are applied in major depression as monotherapy, a response is achieved in only 50–60% of cases [26].

These remission rates of 35–45% [24] and response rates of 50–60% [26] relate to a single trial of a single medication and do not speak directly to the prevalence of TRD, especially when the definition calls for the trial of more than one medication [27]. Nevertheless, these figures do indicate that a satisfactory outcome using currently available monotherapies may be difficult to achieve.

The clinical practice guideline (CPG) of the Royal Australian and New Zealand College of Psychiatrists on the treatment of depression [28] is an authoritative document. Based on the highest levels of evidence, such guidelines must be conservative. They give little advice on the combination of antidepressants. Over the last decade there have been preliminary publications on this topic, which will now be considered.

Objective

The objective of this paper is to explore the literature reporting the drug treatment of TRD and to reproduce information, which would be of interest to clinical psychiatrists and others working in this field.

Method

A literature search was conducted using PubMed and entering the words antidepressant, augmentation, combined antidepressants, treatment resistant depression, and the names of individual antidepressant medications. All available papers and many leading textbooks were examined.

Results

The management of TRD starts with reviewing the diagnosis, using a biopsychosocial approach [4]. Treatment starts with the therapeutic relationship and an alliance with family and friends [28]. A multimodal approach ensures the provision of psychotherapy [29].

With respect to pharmacotherapy, a detailed history is obtained. When an antidepressant has been administered only at an insufficient dose or for an insufficient period, the appropriate increases should be made. In the case of failure of remission, there are at least three options: (i) augment the currently employed antidepressant with a medication, which is not an antidepressant; (ii) change the antidepressant; and (iii) add another antidepressant to the current antidepressant, or commence a combination of antidepressants. This arrangement of options is for purposes of orderly reportage; in clinical practice, options (i) and (ii) are regarded as equal first choices, with option (iii) as a second choice.

Augmentation

Lithium

Lithium is the most extensively studied augmentor (for a detailed summary see Nelson [30]). Seven of nine controlled studies have found lithium to be significantly more effective than placebo. Augmentation may be achieved at relatively low serum levels, and improvement may be observed in some instances within days. Lithium is cheap and is an effective augmentor of a wide range of antidepressants, including the SSRIs. The main problems are those observed in lithium prophylaxis: polyuria; polydipsia; rash; weight gain; non-progressive, non-reversible disturbance of renal function; and relatively low patient acceptance.

There has been some disagreement about the optimum plasma lithium level. Dinan [31], in a dose–response study of the combination of lithium and sertraline, found that some patients responded dramatically at lithium levels as low as 0.3 mmol/L. In contrast, Katona et al. [32] suggested that the benefits of lithium augmentation of fluoxetine were more apparent with lithium levels above 0.4 mmol/L than where this level was not achieved. The consensus appears to be that the lithium level threshold for successful augmentation is lower than that required for prophylaxis.

Thyroid hormone

Thyroid hormone augmentation was first described over three decades ago [33]. One drawback is that the vast majority of work has been done using T3, which is unaffordable in many countries for the treatment of depression. Another is that efficacy has only been fully established in combination with tricyclic antidepressants [TCAs].

Atypical antipsychotics

Atypical antipsychotics may have a place. Risperidone in open studies [34], [35] and olanzapine in an open [14] and a double-blind study [13] have shown promise as augmentors of SSRIs. Tohen and Barker, at a meeting of the American Psychiatric Association [12], described a study in which 833 patients with bipolar depression were randomly allocated to one of three groups: (i) olanzapine; (ii) olanzapine and fluoxetine; and (iii) placebo. Both active treatments were significantly greater antidepressant-effective than the placebo, and the combination was superior to olanzapine alone. In addition to augmenting antidepressant effects, the atypical antipsychotics may have intrinsic antidepressant action, and they reduce insomnia.

Case reports warn that the combination of risperidone and an SSRI may lead to serotonin syndrome [36].

Changing antidepressants

Changing within the same family

Four studies reviewed by Nelson [37] suggest that changing from one SSRI to another can have beneficial effects. However, these are open label, uncontrolled trials.

Changing from SSRI to another family

Currently, a large proportion of patients suffering major depressive episodes are commenced on SSRIs. In such cases, changing to another drug family means moving from a drug with a single action, to a drug with at least two actions. The multiple action drugs are believed to have stronger antidepressant effects [22].

Changing from SSRI to TCA

Change from an SSRI to a TCA has produced benefits. In a doubleblind study [38], 117 patients who failed on sertraline were changed to imipramine, and 44% responded. In a more recent open study [39] 92 patients who had failed 1–5 trials of antidepressants (96% had received SSRIs) were given nortriptyline and 40% responded. The TCAs are effective antidepressants, but they carry side-effects which patients may not accept [40] and they are dangerous in overdose.

Changing from an SSRI to venlafaxine

Venlafaxine is a serotonin and noradrenaline reuptake inhibitor (SNRI). It follows from the observation of Thase et al. [24] that venlafaxine has a higher remission rate than SSRIs, that switching from a single action SSRI to dual action venlafaxine could be beneficial in some cases. Poirer and Boyer [41] selected 122 patients who had failed two previous trials of medication (the majority had received at least one SSRI) and in a double-blind study, gave one half venlafaxine and the other half paroxetine. Remission was achieved in 43% of the venlafaxinetreated patients and only 20% of those receiving paroxetine. A troublesome feature of venlafaxine is withdrawal agitation, which may complicate the discontinuation of this drug.

Changing from an SSRI to mirtazapine

Mirtazapine is a noradrenergic and specific serotonin antagonist. The change to mirtazapine is common in clinical practice, although not supported extensively in the literature. In an open study, Fava et al. [42] studied 69 patients who had failed to respond to SSRIs. After 8 weeks, 48% responded to mirtazapine. The major side-effects of mirtazapine are sedation and weight gain.

Combining antidepressants

The TCAs have multiple mechanisms of action with strong antidepressant effects. In addition, they have other actions which produce unacceptable side-effects. For example, histamine receptor blockade results in sedation, cholinergic receptor blockade produces dry mouth and urinary retention and noradrenaline receptor blockade produces hypotension and reflex tachycardia. In older patients with heart disease, and in overdose, TCA effects on cardiac conduction may prove fatal.

There is reluctance among some psychiatrists to combine antidepressants. This, in part, is a legacy of the past, when the combination of TCAs and monoamine oxidase inhibitors [MAOIs] was considered a risky option.

By combining newer antidepressants, which have relatively fewer unwanted actions, it may be possible to obtain the advantages of multiple mechanisms of action, with fewer side-effects. In the most favourable outcome, the antidepressant actions synergise and an additional action of one antidepressant counteracts the side-effects of another.

There are few double-blind controlled studies on the effects of combinations of antidepressants. In such circumstances, we seek the advice of established experts [43]. Fortunately, many groups have published algorithms. A difficulty of applying algorithms is that patients who are referred to psychiatrists with TRD have usually been trialed on a range of medications and it is impractical to go back and introduce simple level regimens that are unlikely to be effective. However, algorithms do offer authoritative advice on the combination of antidepressants. Five were located. Four (Texas Medication Algorithm Project [44], World Federation of Societies of Biological Psychiatry Guidelines for the Biological Treatment of Unipolar Depressive Disorders [45], Duke Somatic Treatment Algorithm for Geriatric Depression [STAGED] Approach [46] and the RANZCP Clinical Practice Guidelines on the Treatment of Depression [28]) recommended the combination of antidepressants. Table 1 gives details of the levels at which combination is recommended. The fifth (The Berlin Algorithm Project [47]) had its roots in the early 1990s before some of the current drugs became available and interestingly recommends, on the third of four levels, the use of tranylcypromine, an irreversible MAOI.

Table 1.

The recommendations of four authoritative bodies regarding the combination of antidepressants in treatment-resistant depression

In addition, expert committees [48] and individuals [49] recommend simultaneous targeting of both, noradrenergic and serotonergic systems, in the management of partial and non-response to antidepressant therapy. Lam et al. [50] conducted a review of studies of a wider range of combinations of antidepressants in partial and non-response. They pointed to the need for more randomised controlled trials, but found a 62.2% mean response rate.

Certain drug combinations cannot be applied in particular countries because of the unavailability of particular drugs. This is an issue for a number of Asian countries [51]. In Australia, for example, bupropion, recommended by Steffens et al. [46] is not available for use in the treatment of depression.

Combining TCA and SSRI

A number of open studies have suggested this combination to be more effective than either drug alone (for a summary see: Nelson [37]; Fava [52]). The SSRI effect on cytochrome P450 may result in the accumulation of TCAs, with potential for cardiotoxicity. The monitoring of blood TCA levels, EEG and ECG are recommended [53]. This is a burden and additional level of complexity not present with other combinations. It is noted, however, that the SSRIs citalopram and sertraline do not have significant P450 activity.

Combining mirtazapine and SSRI

In a controlled trial, reported at a meeting of the American College of Neuropsychopharmacology, Debonnel et al. [54] reported treating one group of patients with paroxetine and another with mirtazapine, and less than 50% responded. The non-responders were then treated with the drugs combined, and 50% of them responded. In another controlled study Carpenter et al. [55] studied 26 people who had failed to respond to monotherapy (SSRI in most cases), adding mirtazapine or placebo. After 4 weeks, 64% of those receiving mirtazapine responded, significantly more than responded to placebo (20%). Thus, there is evidence that the combination of mirtazapine and SSRI can be both, safe and more effective than monotherapy. A possible advantage of mirtazapine may be a reduction in SSRI-induced sexual dysfunction [56], although this possibility awaits confirmation.

One case report warns that the combination of mirtazapine and an SSRI may lead to serotonin syndrome [57].

Combining reboxetine and SSRI

Reboxetine is a noradrenaline reuptake inhibitor (NRI). Two open trials reported at a meeting of the American College of Neuropsychopharmacology suggested the combination of reboxetine and SSRI may be helpful [58], [59]. This combination appears to be safe [60] and further blind clinical studies are anticipated.

Combining tranylcypromine [MAOI] and stimulants

There is a reluctance to use the irreversible MAOIs because of the risk of hypertensive crisis. Nevertheless, tranylcypromine has a place in the management of TRD. It is effective in major depression unresponsive to TCAs [61] and in bipolar I depression [62]. The MAOIs are considered by patients to be the most effective antidepressant in both, melancholic and non-melancholic depression [63]. The use of MAOIs before ECT is recommended by leading depression treatment algorithms [44–47] and at least one leading textbook [64].

While uncommon in clinical practice, the combination of TCAs and MAOIs has been described as an effective treatment in TRD [65] and is still recommended in extraordinary circumstances [64].

Thase and Rush [11] and Post [64] list the combination of MAOIs and stimulants among the treatment options for ECT non-responders. However, few publications have appeared on this topic over the last decade [66]. This combination does not appear in any of the algorithms and is considered a dangerous combination.

Recently there has been an open study indication that methylphenidate may be combined with SSRI (citalopram) with good effect in the elderly [67]. Modafinil is a relatively new stimulant with little abuse potential, which has been used in narcolepsy and daytime somnolence. It has been used in combination with antidepressants in the treatment of TRD [68] and further studies are being planned.

Combining nefazodone and other antidepressants

Most recently, nefazodone (a 5 HT2 receptor blocker and serotonin reuptake inhibitor) was combined, in an open study [69], with a variety of antidepressants in the treatment of 11 patients (four with TRD, seven with anxiety disorders). Remarkable results were reported. Further studies are required before comments can be made on this combination. Nefazodone has been removed from the market in Canada, apparently on the basis of hepatotoxicity.

Discussion

This review is flawed as material has inevitably been overlooked or has been inaccessible. Efforts were made, however, to access appropriate papers and a decision has to be made as to which reports will be mentioned and which will not. Certain antidepressant drugs have also been left out, such as bupropion and trazodone, for example, as they are unavailable in Australia.

Some interventions were purposefully not included. For example, a vast array of drugs, which have been reported as effective augmentors in at least one study were not included. Lithium, thyroid hormone and the atypical antipsychotics were considered, but buspirone, oestrogen and amantadine were not. The evidence for the former three is stronger than for the latter. There is a necessary word limit, and the inclusion of every potential augmentor would divert attention away from those with a stronger scientific basis.

Published guidelines provide valuable guidance; however, based on the best available evidence, they tend to be conservative. The CPG of the Royal Australian and New Zealand College of Psychiatrists dealing with the treatment of depression [26], for example, provides little advice on the combination of antidepressants. A survey of prescribing preferences in the treatment of TRD among informed US psychiatrists reveals that clinicians quite frequently resort to augmentation and combination of antidepressants [70]. This paper highlights recent publications in the field.

Before prescribing different drugs, the psychiatrist should first check the diagnosis and attend to complicating psychosocial factors. The combination of psychotherapy and medication has become standard practice [7], [70], [71] and need not be restated in this paper. A recent study [72] indicated that augmentation of an antidepressant with cognitive therapy was as effective as augmenting with lithium, although others [73] found that augmenting fluoxetine with cognitive therapy did not significantly reduce relapse rates when compared to fluoxetine alone.

Augmentation and the combination of antidepressants should be conducted with caution. Augmentation with atypical antipsychotics and all combinations of antidepressants require further safety and double-blind, controlled, efficacy studies. However, the studies listed above may indicate that the newer psychotropic medications, with relatively specific actions and improved side-effect profiles, can be used in new combinations to better serve certain patients suffering TRD.

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Medication Options in the Treatment of Treatment-Resistant Depression

Abstract

Keywords

Objective

Method

Results

Augmentation

Lithium

Thyroid hormone

Atypical antipsychotics

Changing antidepressants

Changing within the same family

Changing from SSRI to another family

Changing from SSRI to TCA

Changing from an SSRI to venlafaxine

Changing from an SSRI to mirtazapine

Combining antidepressants

Combining TCA and SSRI

Combining mirtazapine and SSRI

Combining reboxetine and SSRI

Combining tranylcypromine [MAOI] and stimulants

Combining nefazodone and other antidepressants

Discussion

References