The delay in response to antidepressant therapy: A window of opportunity?

Introduction

Antidepressants clearly benefit patients suffering from depressive disorders, but the extent to which they are better than psychological treatments, and in which kinds or types of depression they are most effective, is debateable. In practice, identifying in whom antidepressants will work is an important consideration, as is the question of which antidepressant to choose. Evidence that informs such decisions varies, and given the many options available, treatment is largely determined by exercising clinical judgement. However, one aspect that is seldom considered in detail is the time to antidepressant response. And while whether an antidepressant is effective is a critical consideration, the time it takes to do so is arguably equally important. The reason for the relative lack of interest in the timing of antidepressant response is that most antidepressants are slow to take effect, with antidepressant response typically emerging after approximately 7 days of treatment (Machado-Vieira et al., 2010).

Delayed clinical response

In practice, it is not uncommon for antidepressants to take two or more weeks to invoke a significant response, and the process can take longer still if the antidepressant dose needs to be gradually titrated. Furthermore, beyond this initial delay, response itself is quite unpredictable, and the majority of patients achieve only a partial response at best. In other words, remission is not at all guaranteed, and in natural settings, two, three and sometimes four antidepressant trials are needed to achieve an adequate response that eventually leads to functional recovery (Rush et al., 2006). Hence, clinical discussions usually focus on whether a response is likely to occur and if so whether it will be sufficient to achieve remission. Naturally, this period of having to wait for a potential response to treatment is extremely frustrating for both patients and clinicians alike, and the only practical means by which this delay can be shortened is to ensure that therapeutic levels of the antidepressant prescribed are achieved as quickly as possible. This is partly why so much emphasis is placed on maintaining adherence to antidepressant medication and ensuring that it is taken as prescribed. In addition, patients are usually forewarned of transient side effects so that they are not deterred from continuing treatment. Thus, among the many necessary considerations when commencing antidepressant treatment, the timing of antidepressant response is seldom discussed other than to mention that there is an inherent delay. What is remarkable is that until recently, this delay in antidepressant clinical response could not be adequately explained.

However, it is now known that antidepressants have multiple and complex cellular actions beyond the manipulation of neurochemical transmission. Specifically, antidepressants induce acute pharmacological effects via different molecular mechanisms than when producing effects during longer term administration (Malhi and Mann, 2018). After an initial increase in intrasynaptic concentrations of neurotransmitters, antidepressants produce downregulation of pre-synaptic receptors and increase neuronal firing. Furthermore, antidepressants activate second messenger proteins and modulate neurogenesis by way of regulating proteins such as brain-derived neurotrophic factor (BDNF). In other words, there are sophisticated downstream adaptive processes that require time to take effect, and clinically, this is perceived as an antidepressant response.

Antidepressant response

Within hours of administration, antidepressants produce chemical changes within the brain; but clearly, these do not correspond with clinical response, which typically takes days and weeks to achieve. In practice, this belated response means that there is a considerable wait for clinical antidepressant effects to emerge, and clinicians wanting their patients to get better often resort to a variety of measures to bridge this gap. One tactic is to target distress and lack of restful sleep by prescribing sedatives and anxiolytics. These usually have a rapid effect and improve the quality of sleep and reduce anxiety within a matter of hours. Hence why medications such as benzodiazepines and atypical antipsychotics are widely used in this manner (off-label) (Malhi et al., 2019) despite significant side effects and the potential for addiction/dependency, especially when prescribed long term. In addition, the benefits are usually short-lived, and sustained clinical improvement of depressive symptoms is still very much dependent on gaining a conventional antidepressant response.

But in the face of severe depression, the urgency for clinical improvement and the desire to alleviate distress cannot be overemphasised, and there is a strong imperative for this to be achieved as promptly and safely as possible. Therefore, a new paradigm that highlights the sequential effects of different agents with faster actions has considerable appeal. However, the implementation of such a strategy would necessitate a considerable paradigm change. Therefore, in this brief debate, we argue that a more sophisticated approach to treating depression is required that is evidenced-based and clinically operationalised.

Conceptualising treatment response – a new paradigm

As outlined previously, clinical responses to antidepressants are relatively slow and typically take several days and sometimes weeks to emerge, and therefore, remission and recovery can take months to achieve. Our new paradigm provides an alternative that bridges this gap by considering the different potential windows of treatment response based on the different actions of medications (i.e. immediate, fast and slow). Using a combination of psychotropic drugs when indicated, it is conceivable that an earlier clinical response can be achieved (see Figure 1).

Figure 1.

Windows of treatment response.

Immediate response

It is known that some antidepressant interventions are able to produce an immediate effect and create discernible improvements within a day or two. For example, electroconvulsive therapy (ECT) can have dramatic effects, even after a single treatment. Clearly, an immediate response such as this is hugely advantageous, for example, in instances where the individual is at risk of self-harm because of inanition or threatening behaviour or is extremely agitated and profoundly depressed. Indeed, these are urgent indications for ECT. However, as is sometimes the case, the improvement may not be sustained, and repeated administration of the acutely effective treatment is required. But this may not be feasible. Returning to the example of ECT, debilitating cognitive side effects can sometimes limit further treatment. In addition, the powerful effects of the initial treatment may be difficult to replicate when readministering the same type of therapy. Therefore, in these instances, it may be useful to switch to treatments that have a fast action (faster than conventional antidepressants), but are perhaps not as fast as those that produce an immediate response, and this is what we propose as part of a new paradigm for antidepressant therapy (see Figure 1).

Fast response

Figure 1 illustrates how the fast response bridges the gap between an immediate response and a slow response. A fast antidepressant response may be achieved in a number of ways. First, as already outlined, those agents that have an immediate action can, if circumstances allow, be administered again (repetition). Alternatively, agents that target some of the symptoms of depression (e.g. those related to distress) can be commenced alongside conventional antidepressants. This strategy, which often entails the prescription of atypical antipsychotics, will provide prompt relief from those symptoms that are most troubling.

This new paradigm provides three overlapping windows of response – immediate, fast and slow – and allows framing of a more sophisticated approach to achieving treatment response. Interventions with actions in each of these groups already exist, and newer agents with novel actions are on the horizon. What is perhaps lacking, or lagging behind, is our thinking and conceptualisation of treatment response. It is to this end that we propose a new paradigm for antidepressant treatment in the management of depression. Central to this paradigm shift is a shift of another kind; a willingness to adjust and even switch medications more readily. In addition to being versatile and opening windows of response, this new paradigm also requires a commitment to closing treatment windows in a timely manner so as to ensure that medications are not maintained unnecessarily beyond their optimal effect.

For example, in the new paradigm, a pharmacotherapy regime could include the administration of an agent such as an atypical antipsychotic that has a fast response, which targets some of the symptoms of depression, alongside the commencement of conventional antidepressant. Furthermore, this could be prescribed alongside an intervention that has an immediate action. The latter could be administered as a single administration to stimulate a therapeutic response and medications with a fast action may remain in place for a week or two and then be tapered while ensuring clinical improvement is maintained. This would then allow the slower antidepressant response to gradually emerge.

This strategy clearly necessitates careful consideration of potential drug interactions as well as close monitoring of clinical response and potential side effects. Nevertheless, there are considerable benefits to be gained, such as negating the significant delay in clinical response, ensuring compliance, allowing for closer monitoring of treatment response and side effects, and encouraging a stronger therapeutic alliance.

This new framework not only assists in facilitating a systematic alleviation of depressive symptoms, but by promoting the tailoring of agents to desired clinical outcomes, current understanding into the underlying pathogenesis of depression may be advanced. Furthermore, by viewing the management of depressive symptoms as a process comprising a series of steps with distinct outcomes, the complex relationship between neurobiological changes and clinical responses may be examined with greater precision. Most importantly, however, this approach is likely to focus attention on the timing of treatment response and improve antidepressant outcomes.