Choosing an Antidepressant: Art, Science, and Knowing Your Patient

Choosing an antidepressant can be an art as much as a science, and knowing your patient is key. With several treatment options, few head-to-head trials, and meta-analytic results showing similar effects across agents,¹ the selection of an appropriate intervention for a depressive episode requires individualization and a holistic approach.² Therefore, to better decide on the next treatment step, other elements must be considered based on the evidence available and how this relates to each patient’s unique characteristics.

1. Major Depressive Disorder

First and foremost, confirm the diagnosis of major depressive disorder (MDD). A history of mania or hypomania would significantly change this decision, both due to the different efficacy profile of treatments and the increased risk of affective switching posed by several standard antidepressants. In addition, other conditions may impact mood and either confound diagnosis or limit recovery and should be considered during formulation; examples include adjustment disorder, grief, obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), and substance use disorders (SUDs). This also includes possible underlying medical causes such as hypothyroidism, anemia, sleep apnea, vitamin B12/vitamin D deficiency, hypogonadism, organic syndromes, or adverse effects from preexisting treatments.

2. What to Try First

The first treatment step should balance efficacy, adverse effect burden, accessibility, and patient preferences; in fact, patients may achieve better outcomes when involved in treatment decisions.³ Family treatment history may also be considered.⁴ Often, first-line antidepressants include selective serotonin reuptake inhibitors (SSRIs), vilazodone, vortioxetine, serotonin-norepinephrine reuptake inhibitors (SNRIs), bupropion, and mirtazapine.^5,6 Cost has limited access to vortioxetine, though generics may change this; generic vilazodone is already available.

a. Targeting symptom profile and comorbid conditions

SSRIs are favored as a first step when there is a comorbid anxiety disorder, OCD, PTSD, or premenstrual dysphoric disorder. Fluoxetine’s long half-life suits patients who are more likely to miss a dose. SNRIs may be considered as a first antidepressant choice when peripheral neuropathic pain or fibromyalgia is present. Mirtazapine can be considered when insomnia, low appetite, or nausea are present. Bupropion may be helpful when daytime sedation, seasonal pattern, or interest in smoking cessation are reported.

Some presentations indicate the use of other agents earlier in treatment. When psychotic features are present, it is indicated to combine an SSRI or SNRI with an atypical antipsychotic, with olanzapine and quetiapine having the strongest evidence⁷; psychotic features predict better electroconvulsive therapy (ECT) outcomes and should be considered when a rapid response is needed or alternatives fail. Uniquely in cases of postpartum depression, zuranolone is an FDA-approved option with promising efficacy and a quick onset of response, although accessibility can be an issue at times.

b. Considering the adverse effect profile

Among these agents, citalopram has a higher risk of QTc prolongation, which is dose dependent. This risk is less pronounced with escitalopram. Paroxetine is often deferred in this early stage due to lower tolerability, including anticholinergic burden, weight gain, and possible withdrawal symptoms. SNRIs may be slightly less tolerated than other medications in this group and carry a greater risk of withdrawal symptoms, tachycardia, and high blood pressure, especially at higher doses of venlafaxine. As bupropion may lower the seizure threshold, it should be avoided in patients with a history of seizures or active bulimia. While bupropion can be associated with weight loss, insomnia, and agitation, mirtazapine carries a higher risk of daytime fatigue and weight gain. Bupropion carries the lowest risk of hyponatremia, followed by mirtazapine, and both agents appear to have the lowest risk of bleeding and sexual adverse effects; vortioxetine and vilazodone also pose a lower risk of sexual dysfunction than SSRIs.

3. Treatment Is Not Working: What Now?

Several considerations should precede any change in pharmacotherapy (Table 1).⁸ Then, if adverse effects are minimal and a partial response (≥ 25% improvement) to the initial dose has occurred, the dose may be increased within the therapeutic range.

If the first trial is ultimately deemed unsuccessful, 2 pathways emerge: switching vs augmentation with first-line options. Augmentation saves precious time but increases the burden of adverse effects with 2 medications. Switching, often with cross-titration, avoids polypharmacy at this initial stage of treatment. When switching, no robust evidence supports the need to choose a different antidepressant class, although this may be reasonable if the trial was limited by adverse effects common within that medication group. With neither strategy clearly superior after a first unsuccessful trial, the degree of partial response, tolerability, treatment urgency, and patient preference should drive the choice.

4. Treatment-Resistant Depression vs Difficult-to-Treat Depression

With each unsuccessful trial, the likelihood of improvement in future treatment trials decreases,⁹ which has led to the concept of treatment-resistant depression (TRD).¹⁰ No consensus definition exists, although a starting point usually includes inadequate response after at least 2 antidepressant trials. Only a small number of options have FDA approval specifically for this presentation (Table 2). As major treatment guidelines do not provide direct guidance on selecting the best treatment options for TRD, clinicians must rely on consensus statements, limited TRD clinical trials, and individual expertise.¹¹

a. Beyond the first line

Overall, in addition to the options previously discussed, start to consider augmentation with atypical antipsychotics approved for MDD (Table 3), transcranial magnetic stimulation (TMS), intranasal (IN) esketamine, or intravenous ketamine. In severe cases where rapid response is required, especially in older adults, ECT may be considered earlier in the treatment course.

At this point, the list of reasonable alternatives is long. While not used as frequently since the introduction of agents with higher tolerability, tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) are also an important consideration.¹² Some evidence suggests favorable use of MAOIs in cases of atypical depression and TCAs when melancholic features are present, although stronger evidence is still required. Dextromethorphan-bupropion’s rapid-acting effects and unique NMDA receptor actions offer distinct advantages, although limited data are available on its use in TRD. Other treatment options include augmentation with lithium, thyroid hormone, dopamine agonists, buspirone, and stimulants. In very select cases, when treatment is well tolerated and efficacy is evident without achieving full remission, dosing beyond the FDA-approved maximum can be considered; this requires an individualized approach with close safety monitoring.

b. Adverse effects and comorbidities in TRD treatment

Metabolic disease may limit augmentation with atypical antipsychotics, especially olanzapine and quetiapine; for such patients, bupropion and dextromethorphan-bupropion are notable options. Patients under greater risk of arrhythmia, QTc prolongation, and anticholinergic effects may face challenges with TCAs, which are usually avoided. Due to the risk of transient elevations in blood pressure and intracranial pressure, esketamine/ketamine is contraindicated if aneurysmal vascular disease, arteriovenous malformation, or a history of intracerebral hemorrhage is present¹³; data are also more robust in younger adults, who carry fewer cardiovascular concerns. Similarly, MAOIs require attention to hypertensive reactions, as well as drug interactions and tyramine dietary counseling. A personal history of seizures is a barrier for TMS, whereas SUDs would be a concern when considering esketamine/ketamine.

c. When tolerability becomes a major barrier

When trials fail repeatedly due to sensitivity to medications’ adverse effects, consider interventions with minimal systemic effects, such as at-home neuromodulation devices, TMS, or reducing daily medication burden with IN esketamine or IV ketamine. Although findings from studies so far have not supported improved outcomes from choosing options based on pharmacogenomic testing, it may help identify cases of abnormal metabolizer status; guidelines are available to inform dosing in specific CYP450 metabolism profiles.¹⁴ Finally, serum therapeutic levels may play an important role in cases of bariatric surgery, especially when a therapeutic range has been established, such as with TCAs.

5. Concluding Thoughts

There have never been so many options for antidepressant treatment. The list continues to grow, with rapid-acting agents, expanding brain stimulation, and greater access to newer medications on the horizon. Having extensive options raises the value of the clinical skills needed to navigate them: careful formulation, knowledge of treatment nuances, and a strong ability to tailor decisions based on––and with––the person in front of you.

Dr Marques is a Mayo Clinic–trained psychiatrist with clinical expertise in the field of mood disorders.

Dr Singh is an associate professor of psychiatry at Mayo Clinic in Rochester, Minnesota.

Conflict of Interest Disclosures

Dr Singh has received research grant support from Mayo Clinic, the National Network of Depression Centers, Breakthrough Discoveries for Thriving with Bipolar Disorder (BD2), and the National Institutes of Health (NIH). He is a KL2 Mentored Career Development Program scholar, supported by CTSA Grant Number KL2TR002379 from the National Center for Advancing Translational Sciences. Dr Marques reports no potential conflicts of interest.

Use of AI-Assisted Technologies in the Writing Process: In the writing of this manuscript, the authors used Claude Sonnet/Fable 5 by Anthropic to improve the readability of the draft. The authors have reviewed the content and take full responsibility for its accuracy.

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