Switching or Augmentation Strategies in the Treatment of Major Depressive Disorder – What Does the Evidence Tell Us?

WHAT DOES STAR*D TEACH US?

The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) STAR*D trial was designed to determine the best strategy after a non-response to an initial SSRI treatment [Fava et al., 2003], [Rush et al., 2004]

Important findings were: 

• Only 49% and 37% of adult patients with MDD reported response and remission, respectively, of their symptoms with their first treatment step. [Rush et al., 2006]
• Longer times than expected were needed to reach response or remission.
• Suppose a modest improvement (e.g., ≥20% reduction) is present; in that case, a dose increase (if tolerated) at 6 weeks or simply further exposure (up to 10 weeks) may help a sizable number of patients to at least respond, if not achieve remission, by 12 weeks.
• The STAR*D study showed that success rates decline with each successive treatment step, with the likelihood of remission substantially decreasing after two vigorous medication trials. Remission is likely to require more complicated medication regimens.

Other studies indicate that at least 30% of patients will either not respond to or only partially respond to their initial treatment, irrespective of the antidepressant. [Bauer et al., 2013]

After the initial SSRI treatment following were the strategies employed at different levels.

Level 2:

• Switch to Bupropion OR Venlafaxine OR Sertraline OR Cognitive Behavioural Therapy (CBT)
• Augment with Bupropion OR Buspirone OR Cognitive Therapy

Level 3: 

• Switch to Mirtazapine OR Nortriptyline
• Augment with Lithium OR T3

Level 4:

• Switch to Tranylcypromine OR Mirtazapine + Venlafaxine

Key points from STAR*D about Switching or Augmentation: [Rush, 2007] 

• Switching and augmentation are reasonable options for patients after an initial antidepressant treatment has failed.
• Patients had clear preferences at both the second and third levels in STAR*D. Those who fared better in the previous step and evidenced minimal intolerance preferred augmentation. Patients who experienced little benefit or significant side effects with the initial treatment preferred to switch.
• A within-class switch (e.g., citalopram to sertraline) or an out-of-class switch (e.g., citalopram to bupropion-SR) was effective.
• A switch to a dual-action agent (e.g., venlafaxine-XR) was also effective.
• At level 2, despite substantial pharmacologic differences between Bupropion and Buspirone, this did not translate into significant clinical differences in efficacy.
• At level 3, a medication switch was far less effective than a medication switch in the second step.
• At Level 3,  T3 augmentation did as well or better than lithium.
• At Level 4, Venlafaxine plus Mirtazapine was associated with greater symptomatic improvement and less attrition because of side effects compared to Tranylcypromine (MAOI). Venlafaxine (extended-release) was started at a low dose, built up to a mean dose of 210.3 mg/day in combination with Mirtazapine, which was gradually titrated to a mean of 35.7 mg/day.

Since remission must be the goal of treatment—a notion clearly supported by the STAR*D follow-up results—different combinations/augmentations at the first or second steps might well increase remission rates in more patients, either because different drugs target different patients or because the combination/augmentation is simply a pharmacologically more powerful and broader spectrum antidepressant.

The gap between what we do in practice and what we know is very large. We insist that remission is our goal, yet we do not routinely carefully measure symptoms in practice to determine if remission occurs. Yet we know that “better but not remitted” consistently leads to a worse prognosis than full remission. We often underdose or poorly titrate medication. Finally, we often combine treatments in practice, yet very few trials have assessed either safety or efficacy of these efforts. Analogous to treating hypertension, diabetes, or many other medical conditions, our patients deserve every chance to reach remission. “Less hypertensive” is not the goal of treatment of hypertension. Nor should “less depressed” be the goal for our depressed patients. [Rush, 2007] 

However, the rationale and design of this large-scale STAR*D study were published in 2003 and 2004. [Fava et al., 2003], [Rush et al., 2004]

Therefore, although the STAR*D reports have been incorporated into treatment guidelines worldwide, they do not include more recent clinical evidence on pharmacologic adjuncts, such as atypical antipsychotics or psychostimulants.

STUDY COMPARING SWITCHING TO BUPROPION-SR OR AUGMENTING WITH BUPROPION-SR OR ARIPIPRAZOLE - WHO AND WHAT WAS STUDIED?

The Veterans Affairs (VA) Office of Research and Development and the VA Centralised Institutional Review Board approved a study to analyse three alternative MDD treatment strategies. [Mohamed et al., 2017] 

This included switching to bupropion-SR (sustained-release) or augmenting current treatment with bupropion-SR or aripiprazole, an atypical antipsychotic, after patients failed at least one antidepressant trial.

Bupropion is a Noradrenaline and Dopamine Reuptake Inhibitor(NDRI). Bupropion – Mechanism of Action | Psychopharmacology | Clinical Application

Aripiprazole is a partial dopamine agonist. Aripiprazole – Mechanism of Action, Psychopharmacology and Clinical Application

The study—VA Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D)—was a multisite, randomised, single-blind, parallel-assignment trial that involved 1552 patients that were unresponsive to at least one course of antidepressants.

Eligibility was based on DSM-IV-TR criteria and the 9-Item Patient Health Questionnaire (PHQ-9) scores. Patients were randomised at 35 different medical centres to either: switching to bupropion-SR, augmenting current treatment with bupropion-SR, or augmenting current treatment with aripiprazole.

Bupropion-SR dose: Treatment intervention doses of bupropion-SR in the augment-bupropion group started from an initial 150mg bupropion-SR dose and titrated to either 300 mg or 400 mg bupropion-SR.

Aripiprazole Dose: In the augment-aripiprazole group, the initial dose was 2mg and this was titrated to 15 mg aripiprazole.

Outcome measures: 

• The primary outcome was remission, which describes symptom remission as measured by the 16-Item Quick Inventory of Depressive Symptomatology-Clinician Rated (QIDS-C₁₆ score ≤5 at two consecutive visits).
• Secondary outcomes included a response which was a reduction of ≥50% in QIDS-C₁₆ and a Clinical Global Impression (CGI) Improvement scale rating of 1 or 2 at any scheduled visit.

WHAT WERE THE FINDINGS?

Of the 7234 patients (Patients were 85% male and 15% female) screened for antidepressant-resistant MDD, 1522 were randomised to one of the three treatment groups:

• Switching to bupropion-SR (n=511)
• Augmentation with bupropion-SR (n=506) OR
• Augmentation with aripiprazole (n=505).

Results: 

Patients achieving response (≥50% in QIDS-C₁₆ ):

• Switch group: 62.4%
• Augment Bupropion group: 65.6%
• Augment Aripiprazole group : 74.3%
• Statistically, this response was significantly higher for the augment-aripiprazole group compared to both the switch group and the augment-bupropion group

Patients achieving response (Clinical Global Impression (CGI) Improvement scale rating of 1 or 2 at any scheduled visit):

• Switch group: 69.7%
• Augment Bupropion group: 74.3%
• Augment Aripiprazole group : 79.2%

Patients achieving remission after 12 weeks :

• Switch group: 22.3%
• Augment Bupropion group: 26.9%
• Augment Aripiprazole group : 28.9%
• Statistically, this result was significantly higher for the augment-aripiprazole group compared to the switch group but not when it was compared to the augment-bupropion group.

Withdrawals from each group were recorded, and this showed that only 353 (69.1%) completed 12 weeks of the switch therapy; 406 (74.7%) completed 12 weeks of the augment-bupropion treatment; and 378 (80.4%) completed 12 weeks of the augment-aripiprazole therapy.

Withdrawal due to lack of treatment response:

• Switch group: 9.6%
• Augment-bupropion group: 5.5%
• Augment Aripiprazole group : 2.6%

Withdrawal due to drug-related adverse events (AEs):

• Switch group: 10%
• Augment-bupropion group:  7.3%
• Augment Aripiprazole group: 5.3%

Non-serious Side Effects: 

There were 4356 non-serious AEs recorded, and the common side effects in each group were:

• Switch group: nausea, irritability, and hypomania
• Augment Bupropion group: anxiety, decreased appetite, dry mouth and increased blood pressure.
• Augment Aripiprazole group: fatigue, increased appetite, increased weight (>7% increase in weight), akathisia, and somnolence

Serious Side Effects: 

165 patients experienced 207 serious AEs, including eight deaths during or within 30 days of the study, including one completed suicide. However, the researchers concluded that none of the deaths were related to the study medication.

SUMMARY OF THE VAST-D

• The augment Aripiprazole group showed a statistically significant higher remission rate during 12 weeks of treatment compared to switching to Bupropion monotherapy after 12 weeks in depressed patients that had failed at least one antidepressant trial.
• Response rates were also higher for the augment Aripiprazole group, which was statistically significant compared to both switch and augment Bupropion groups.
• The lowest withdrawal rates were also observed for the augment-Aripiprazole group showing that this treatment strategy was well tolerated.

STRENGTHS AND LIMITATIONS

Strengths and Limitations

• This study is sufficiently powered and well-controlled and, for the first time, compares the efficacy of switching and augmentation between two pharmacological agents that were not compared in the STAR*D study.
• However, this trial is also limited because only one antidepressant (bupropion-SR) and one atypical antipsychotic (aripiprazole) were evaluated. Therefore, the study’s results only apply to bupropion-SR and aripiprazole and not to any other NDRIs or atypical antipsychotics.
• Although the sample size number was achieved, the differences in the primary outcome between the groups were small in magnitude. It is, however, possible that the switch group was affected by withdrawal symptoms from the previous treatment regime, which may have affected the statistical power of this group’s data.

SWITCH OR AUGMENT IN GERIATRIC TREATMENT RESISTANT DEPRESSION?

A recent study that examined this question showed: [Lenze, 2023].

• Adding aripiprazole to existing antidepressants helped improve well-being significantly more than switching to bupropion in older adults with treatment-resistant depression over 10 weeks.
• The aripiprazole-augmentation group had a higher remission rate at 28.9%, followed by the bupropion-augmentation group at 28.2%, and the switch-to-bupropion group at 19.3%.
• Bupropion augmentation had the highest incidence of falls.
• If bupropion augmentation or switching failed, lithium augmentation or switching to nortriptyline had similar effects on well-being and remission.

HOW LONG SHOULD ONE WAIT FOR RESPONSE AFTER INITIATION OF AN ANTIDEPRESSANT?

According to the Windows of Antidepressant Response Paradigm (WARP), response to treatment can be conceptualised into three distinct periods: [Malhi et al., 2020]

• Immediate (1–2 days)
• Fast (up to 1 week) and
• Slow (1 week onwards)

Observations strongly support the 2-week principle. Increasing evidence suggests that many patients with MDD show an improvement in symptoms within 2 weeks of starting treatment. [Blier, 2009]

This two week duration is important as early responders are at least three times more likely than others to become sustained responders. [Stassen et al., 2007]

Since lack of early response is predictive of poor response later, and poor response adversely affects disease course and can result in chronicity, lack of improvement within 2-4 weeks should alert us to the need for prompt change in therapy. [Kudlow et al., 2014]

We suggest that clinicians should think about the possible need to change treatment as early as 1 week and certainly consider it after 2 weeks of non-response. Waiting for 4 weeks is, in our opinion, too long. [Baune & Falkai, 2021]

Several guidelines agree that insufficient response can be defined within 2–4 weeks of initiating treatment. [MacQueen et al., 2017]

The Canadian Network for Mood and Anxiety Treatments (CANMAT) recommends: [Kennedy et al., 2016]

• No response in 2-4 weeks to initial treatment – Increase dose
• If response remains inadequate: Change of antidepressant or adjunctive medication (for patients with early treatment resistance)

The Treatment Algorithm Group from Australia and New Zealand :

• Patients showing <20% improvement after 3 weeks after partial or no response at 2 weeks:  Increase dose or change antidepressant. [Boyce et al., 2019]

EVIDENCE FOR SWITCHING ANTIDEPRESSANTS

A recent large prospective study suggests that switching to mirtazapine from sertraline is more beneficial than escalating the dose of sertraline. [Kato et al., 2018]

Furthermore, switching between escitalopram and nortriptyline (in either direction) may be beneficial if the initial medication is ineffective. [Köhler-Forsberg et al., 2019]

However, contrary to these findings, a systematic review of three randomised controlled studies that compared switching vs continuation of the same antidepressant failed to show any significant overall advantage for switching. [Bschor et al., 2018]

Despite a limited evidence base to support this strategy, switching medication, and using an antidepressant from a different class, is a common and worthwhile strategy for managing partial or nonresponse. [Boyce et al., 2020]

Indications for Switching:

• The first antidepressant trial
• Poorly tolerated side effects to the initial antidepressant.
• No response (<35% improvement) to the initial antidepressant.
• More time to wait for a response (less severe, less functional impairment).
• The patient prefers to switch to another antidepressant.

Which antidepressant to prescribe if a switch is considered?

RCTs have found that switching to an antidepressant from a different class improves response and remission rates when switching for either non-response or intolerability reasons. [Malhi et al., 2021]

In-class switch:

• When the first antidepressant has to be ceased because of intolerable side effects.
• Patients with mild to moderate depression.

Out of Class Switch:

• The patient has severe depression or melancholia (e.g. SSRI to SNRI).
• Switch to a broad spectrum agent for patients with melancholic depression, e.g. SNRI, TCAs etc. Read more about the management of melancholic depression. 
• The REVIVE study showed that treatment with vortioxetine vs agomelatine improved clinical outcomes in patients with a partial response after one course of an SSRI or SNRI (remission rate 55.2% at week 12). [Montgomery et al., 2014]

Techniques for switching : [Keks et al., 2016].

When switching agents, clinicians should consider agents’ half-lives and their unique psychopharmacological properties.

The aim is to avoid or minimise withdrawal symptoms while tapering and avoid drug interactions during switching.

The article below covers ways to minimise withdrawal symptoms and half-lives of SSRIs.

Diagnosis and Management of Antidepressant Withdrawal – Understanding the Hyperbolic Curve and SSRI withdrawal.

Direct switch:

• Stop the first antidepressant (AD) abruptly, and start the new antidepressant the next day.

Taper and switch immediately:

• Gradually taper the first antidepressant (AD), then start the new antidepressant immediately after discontinuation.

Taper and switch after a washout:

• Gradually withdraw the first antidepressant, then start with the new antidepressant after a washout period.

Cross-tapering:

• Taper with the first antidepressant (usually after 1-2 weeks or longer), and build up the dose of the new antidepressant simultaneously.

Switching Guide from Australian Prescriber: [Keks et al., 2016].

Click image to download.

EVIDENCE FOR AUGMENTATION OF ANTIDEPRESSANTS

There are several augmentation options available for clinicians. Newer modalities such as neurostimulation, hormones, and rapid-acting antidepressants (e.g. IN esketamine and ketamine) are all helpful augmentation strategies. Augmentation with psychological therapies and lifestyle modifications should always be a part of the overall treatment of depression. Not all augmentation options have been well studied.

The principle of augmentation is based on the extraction of synergy.

Combining drugs with different mechanisms promotes “pharmacologic synergy,” whereas combining drugs with similar mechanisms may simply promote unnecessary redundancy. The second principle is understanding the mechanisms underlying the drugs’ side effects. Successfully combining drugs with opposing side-effect profiles will promote tolerability. In fact, the best drug combinations obey both rules, namely, they offer a synergistic boost to efficacy because of the different mechanisms of action of each agent and increased tolerability because of side effects that cancel one another out. [Stark, 2006]

Augmentation should be differentiated from polypharmacy.

The term ‘polypharmacy’ generally carries a negative connotation which is actually more correctly related to the notion of irrational polypharmacy. Less mention is usually made, however, of rational polypharmacy which involves pharmacodynamic synergism and has long been established as good practice in various clinical fields such as oncology, anaesthesia, hypertension, pain management and so on. [Restifo, 2012]

According to the RANZCP Mood Disorder Guidelines: [Malhi et al., 2021]

• Lithium and second/third generation antipsychotics remain preferred options for augmentation in treatment-resistant depression.
• Clinical observations encourage liothyronine (T3) even though objective research studies remain negative. [Lorentzen et al., 2020]; Parmentier and Sienaert, 2018).
• Evidence for the use of Modafinil and Methylphenidate is emerging [Bassett et al., 2019], and stimulants may be helpful for the management of ‘treatment-resistant depression.
• Minocycline is also promising as an adjunctive medication [Husain et al., 2017], as are oestrogen supplements, which have a role as augmenting agents in some perimenopausal women. [Maki et al., 2018]
• In addition, a combination of ‘wake’ (total sleep deprivation) and light therapies (facilitating sleep cycle with light exposure) have also shown promise in managing poorly responding depression, especially when diurnal mood variation is a prominent feature of the illness. [Kragh et al., 2018]

Indications for Augmentation: 

• 2 or more antidepressant trials.
• The initial antidepressant is well tolerated.
• Partial response (>25% improvement) to the initial antidepressant.
• Specific residual symptoms or side effects to the initial antidepressant that can be targeted.
• Less time to wait for a response.
• The patient prefers to add on another medication.

Which agent to prescribe if an augmentation strategy is considered?

STAR*D Trial:

• Bupropion was an effective augmentation agent as well as an effective monotherapy option.
• Additional augmentation strategies of benefit included T3 and the combination of Venlafaxine plus Mirtazapine.

VAST-D Trial: 

• Augmentation with aripiprazole was an effective and well-tolerated strategy

Optimizing antidepressants for TRD in older adults (OPTIMUM) Study: [Lavretsky et al., 2022]

• Augmentation with Aripiprazole and augmentation with Bupropion had roughly similar effectiveness and were more effective than a switch to Bupropion.
• All three strategies were roughly equal in their risks, such as falls and serious adverse events.
• In the second step of the trial, lithium augmentation and a switch to nortriptyline were roughly equivalent in both effectiveness and risks.

Two recent systematic reviews looking at augmentation strategies for treatment-resistant MDD reported the following:

Nunez et al., 2022:

• Atypical antipsychotics, lithium, thyroid hormones, modafinil, and lisdexamfetamine were effective augmentation agents.
• Lithium and thyroid hormones are important augmentation strategies but are underutilised.

Scott et al., 2022:

• Lithium, aripiprazole and quetiapine are effective current first-line augmenters for TRD.
• Efficacy was most apparent for aripiprazole, esketamine, mirtazapine, olanzapine, quetiapine, risperidone and CBT.
• The largest effect sizes were from Cognitive Behavioural Therapy (CBT), Esketamine and Risperidone.
• Esketamine has the potential to be upgraded in the algorithm for TRD based on this review.
• Bupropion is effective and well-studied in early-stage TRD, but this is not reflected in guidelines adequately. The authors urge consideration of Bupropion as an augmentation agent in TRD.
• Other agents with high effect sizes but smaller sample sizes included mecamylamine and olanzapine and fluoxetine combination (OFC) bupropion, buspirone, cariprazine and lithium.
• There was considerable heterogeneity in the studies examining brexpiprazole, lithium, mecamylamine, olanzapine and lisdexamfetamine; however it is essential to recognise the real-world effect of such heterogeneity is likely to be marked differences in response between patients. Hence the authors caution against a “one size fits all” approach.

We urge large-scale investigations of understudied agents showing promise, including modafinil, S-adenosyl-L-methionine and cognitive behavioural analysis system of psychotherapy. Finally, we hope that our findings are considered in updating treatment guidelines, particularly in the potential for upgrading (es)ketamine, CBT, mecamylamine and bupropion. [Scott et al., 2022].

The choice of augmentation strategy, thus, should take into account the clinical nature and severity of depression, the etiological factors, tolerability profile, cost and complexity.

Recognising the nature of depression is important, as the presence of psychotic features should prompt augmentation with antipsychotic medication. This might seem intuitive, but according to the STOP-PD study, studies have shown that only 5% of patients with psychotic depression receive a good combination of an antidepressant and an antipsychotic. [Andreescu et al., 2007]. 

Furthermore, melancholic depression treatment requires broad-spectrum antidepressants, i.e. agents that target serotonergic, noradrenergic and dopaminergic pathways (e.g. TCAs, SNRIs or combinations such as Venlafaxine plus Mirtazapine)

For example, in melancholic depression, adding Bupropion-SR to an SSRI ‘creates’ a broad spectrum agent as Bupropion increases levels of NA and DA in the synaptic cleft via NART and DAT blockade while the SSRI increases synaptic serotonin. This synergy, therefore, can increase therapeutic efficacy where the whole is greater than the sum of its parts.

On the other hand, a combination of SNRI plus SSRI would be contraindicated due to the increased risk of serotonin syndrome.

We have covered a range of augmentation strategies in the article on melancholic and psychotic depression. 

The below article also covers a case of augmentation strategy:

How to Treat Depression by Using Biological Deconstruction – Case Files of a Patient with OCD and Depression

SUMMARY

Clinicians often perceive the general algorithm for the treatment of MDD to show that monotherapy treatment should be attempted before augmentation in the case of non-response. However, both switching and augmentation may be viable strategies after an initial non-response to medication. Based on the evidence, there are a number of pharmacological options and CBT that clinicians can choose as augmentation strategies. In this article, we focus on pharmacological options predominantly. rTMS and ECT are other treatment options for clinicians to consider.

Firstly, it is essential to recognise that response to any initial treatment should be evaluated early (1-2 weeks) rather than late, as a late response is associated with chronicity.

Secondly, proactive strategies to treat partial or non-response should be implemented early (within 2-4 weeks) rather than after, as early responders are three times more likely to become sustained responders. Hence clinicians should consider dose increase, switching or augmentation early in treatment.

Both switching and augmentation strategies show evidence, and the decision to switch or augment should be an individualised, shared decision-making process.

The decision should consider the symptom severity, the patient’s disability, and the cost and complexity of treatment choice.