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The DSM-5 diagnostic criteria for major depression can be conceptually divided between “active/positive” symptoms (negative rumination, guilt, agitation, insomnia) and “passive/negative” symptoms (cognitive slowing, fatigue, hypersomnia, amotivation, anhedonia).^1,2 Despite this heterogeneity, many primary care providers follow a standard algorithm: try an SSRI or two, and if inadequate response, refer to psychiatry. This approach fails to account for the reality that depression presents very differently across patients, and that medication selection should be tailored to the specific symptom constellation.²

We take a symptom-based approach, determining whether your depression is predominantly passive (low energy, excessive sleep, cognitive fog, lack of motivation or pleasure) or active (negative thoughts, guilt, restlessness, insomnia), as well as whether it’s acute or chronic. This allows us to select medications that target your specific symptoms rather than just taking a default approach for all patients with “depression”²

CRITICAL: Ruling out underlying medical causes. For patients with predominantly passive/negative symptoms, we strongly recommend a sleep study in most cases to rule out obstructive sleep apnea (OSA). OSA is dramatically underdiagnosed and can present identically to depression—causing fatigue, cognitive impairment, low motivation, and mood disturbance.² Similarly, in perimenopausal or postmenopausal women, hormonal changes can produce depressive symptoms that respond poorly to antidepressants alone but dramatically improve with hormone replacement.^5,6,7 Treating someone with undiagnosed OSA or untreated menopause with antidepressants alone often provides minimal benefit, whereas addressing the underlying cause can be transformative.^2,7 We also suggest screening for thyroid dysfunction, vitamin D deficiency, and testosterone deficiency (in men) before committing to long-term antidepressant therapy.²

For predominantly passive/negative depression (fatigue, hypersomnia, anhedonia, amotivation, cognitive slowing) – “Atypical Depression”:

Wellbutrin (bupropion) – A moderate norepinephrine-dopamine re-uptake inhibitor and nicotine modulator that increases energy, motivation, concentration, and pleasure response without the sedation, weight gain, or sexual dysfunction of SSRIs.^8,9 Often our first-line choice for passive depression and anhedonia.⁸ Works within 1-2 weeks, faster than SSRIs.¹⁰ Can be activating in a therapeutic way for patients stuck in low-energy states.¹⁰

Atomoxetine (Strattera) – A potent norepinephrine reuptake inhibitor primarily indicated for ADHD, but potentially effective for atypical depression with prominent executive dysfunction, poor concentration, and low energy.^11,12 Doesn’t have abuse potential and provides sustained noradrenergic enhancement.¹¹ Takes up to 6-8 weeks for full effect but can significantly improve motivation and cognitive function and some patients may notice immediate improvement.¹²

Fetzima (levomilnacipran) – A strong SNRI with preferential norepinephrine activity, useful when energy and motivation are impaired alongside mood symptoms.¹³

Dopamine agonists (pramipexole, ropinirole) – Primarily indicated for Parkinson’s disease and restless legs syndrome, but increasingly used off-label for treatment-resistant depression with severe anhedonia (inability to experience pleasure). Works by directly stimulating dopamine receptors rather than just preventing re-uptake. Can be remarkably effective for patients who don’t respond to traditional antidepressants, particularly when loss of interest and pleasure is the dominant symptom. Require careful titration and monitoring.¹⁴

Selective/Transdermal MAOIs – While traditional MAOIs require strict dietary tyramine restrictions, newer options are much safer. Selegiline (Emsam patch) at low doses is a selective MAO-B inhibitor that is less likely to induce hypertensive crisis and provides excellent efficacy for atypical depression with often less side effects than other medications. The transdermal delivery avoids first-pass metabolism, further improving the safety profile. MAOIs are particularly effective for atypical depression that hasn’t responded to other agents and are underutilized due to outdated fears about the older, non-selective formulations.^15,16

Trintellix (vortioxetine) A multimodal medication that combines the mechanisms of SSRIs with others that can minimize side effects and fight negative symptoms of depression.¹⁷

For predominantly active/positive depression (rumination, guilt, agitation, insomnia, anxiety):

SSRIs (Serotonin Reuptake Inhibitors)– This group is extremely potent in treating emotional anxiety and depression with more “active or emotional symptoms”. They come with a downside of delayed efficacy and more side effects, especially when first starting, versus other medications that are targeted at specific parts of the serotonin system.^3,4,18

SSRIs more broadly increase serotonin levels through re-uptake inhibition. However, rather than treating a “deficiency”, new evidence suggests they work by stabilizing the quality of serotonin signaling, and down regulating problematic parts of the serotonin system that may be over activated.¹⁸ Some, SSRIs, particularly Prozac may also raise levels of neuroplasticity promoting growth factors (BDNF) and neurosteroids.¹⁸

This results in delayed efficacy of up to 6-8 weeks and possibly short term worsening of symptoms as problematic parts of the system are triggered before they are overwhelmed and eventually downregulate.^3,4,19 Examples include escitalopram, sertraline, and fluoxetine. We generally favor Prozac (fluoxetine) due to it’s unique mechanisms in treating depression in addition to re-uptake inhibition.¹⁸

SNRIs – These work similarly to SSRIs, but also inhibit inhibit re-uptake of noradrenaline, raising its concentration.^20,21 They may be particularly helpful for patients who also have negative/passive symptoms of depression as described, and also for treating rumination. Examples include venlafaxine and duloxetine.^20,21

Gepirone (Exxua) – A 5-HT1A receptor agonist is similar to buspirone in that is more targeted, but smaller in scope than SSRIs. This makes it somewhat weaker, but greatly reduces quality of life side effect burden and possibly speeds effectiveness.^22,23,24 Has stronger 5-HT1A agonism than buspirone but less dopamine modulation.²⁴ Requires initial EKG and baseline labs due to potential for QT prolongation, with periodic monitoring during treatment.²² Particularly good for patients with active/positive depressive symptoms (rumination, guilt, anxiety, agitation) who can not tolerate SSRIs or prefer other options. Still takes several weeks for full antidepressant effect.^22,24

Trintellix (vortioxetine) – As briefly introduced above. Trintellix combines serotonin reuptake inhibition with the mechanism of Gepirone (5-HT1A), and Zofran (5-HT3) and several others all in one pill. This unique mechanism provides antidepressant and anxiolytic effects while potentially enhancing cognitive function, reducing side effects (versus SSRIs), and resulting in faster action (though still on the order of weeks)¹⁷

Mirtazapine – A direct acting antiserotonergic agent (blocks problematic serotonin receptors 5-HT2A, and 5-HT2C) that particularly useful when anxiety coexists with insomnia, nausea poor appetite, or depression. Works faster than SSRIs (often within days) and addresses multiple symptoms simultaneously. It is likely to cause increased appetite and can be sedating, but is less likely to have other side effects than SSRIs. Like Buspirone it generally enhances rather than reduces sexual function.^25,26

Trazodone – An antidepressant that is somewhat of a middle ground between mirtazapine and SSRIs with both a moderate degree of serotonin re-uptake inhibition and receptor antagonism. Can be added to other antidepressants specifically for sleep when insomnia is resistant, allowing the primary antidepressant to be chosen based on daytime symptoms. Has some antidepressant effects on its own at higher doses. We generally prefer mirtazapine alone or in combination with an SSRI/SNRI unless side effects are intolerable.^27,28

For mixed presentations or treatment-resistant cases:

Combination therapy – We frequently combine medications with complementary mechanisms. Common examples: Wellbutrin + SSRI (addressing both dopamine/norepinephrine and serotonin), Wellbutrin or (S)NRI+ mirtazapine (“California rocket fuel” for severe depression), or augmentation with low dose aripiprazole (Abilify) or brexpiprazole (Rexulti).^29,30,31,32

Tricyclic antidepressants (TCAs) – Older medications like nortriptyline or desipramine are often overlooked but can be highly effective, particularly for melancholic depression or when insomnia and pain are prominent features. While they have more side effects than newer agents (dry mouth, constipation, potential cardiac effects), they’re often more effective than SSRIs for certain presentations. Require baseline EKG and occasional monitoring but are safe when used appropriately. We favor secondary amines (nortriptyline, desipramine) over tertiary amines (amitriptyline, imipramine) due to better tolerability.^2,3

Auvelity (dextromethorphan-bupropion) – A novel combination pairing dextromethorphan (NMDAR antagonist and sigma-1 agonist) with bupropion (which provides dopamine/norepinephrine reuptake inhibition and stabilizes dextromethorphan levels.³³ This creates ketamine-like glutamatergic effects promoting rapid synaptogenesis and neural plasticity, combined with dopaminergic/noradrenergic enhancement—without ketamine’s dissociative effects or need for IV administration.^33,34 Shows separation from placebo by week 1 with ~54% response rates by week 6.^33,35,36

Particularly effective for depression with prominent anhedonia (“I feel nothing” rather than “I feel sad”), severe amotivation, psychomotor slowing, cognitive fog, or residual emotional blunting on SSRIs. For early treatment-resistant depression (after 1-2 failed trials), this represents a genuine mechanism switch rather than cycling through more SSRIs.^3,34

Contains bupropion with similar warnings.^9,33 May be non-ideal for highly agitated patients who don’t tolerate activation well, but can be a great option for anhedonia-predominant depression or for patients who can’t wait 6-8 weeks for improvement.^33,35 If Auvelity isn’t affordable, we can discuss prescribing it’s two ingredients separately. However this off‑label strategy, may not be identical and requires careful risk review.³³

Our approach is to match the medication mechanism to your specific symptom profile and neurobiological needs—not to reflexively prescribe medications that may be suboptimal or even counterproductive for your particular type of depression. We also investigate and address underlying contributors like sleep disorders, hormonal imbalances, and metabolic dysfunction, recognizing that depression is often multifactorial and requires comprehensive evaluation beyond simply prescribing antidepressants.^2,3

References

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Publishing; 2013.

2. StatPearls Publishing. Major depressive disorder. In: StatPearls [Internet]. Link. Accessed January 18, 2026.

3. Kovich H, Kim W, Quaste AM. Pharmacologic treatment of depression. Am Fam Physician. 2023;107(2):173-181. Link. Accessed January 18, 2026.

4. National Institute for Health and Care Excellence (NICE). Depression in adults: treatment and management (NG222). Link. Accessed January 18, 2026.

5. Miller KE. Estrogen treatment for depression in perimenopause. Am Fam Physician. 2002;65(4):689-690. Link. Accessed January 18, 2026.

6. Schmidt PJ, Ben Dor R, Martinez PE, et al. Effects of estradiol withdrawal on mood in women with past perimenopausal depression: a randomized clinical trial. JAMA Psychiatry. 2015;72(7):714-726. doi:10.1001/jamapsychiatry.2015.0111. Link. Accessed January 18, 2026.

7. Gordon JL, Rubinow DR, Eisenlohr-Moul TA, et al. Efficacy of transdermal estradiol and micronized progesterone in the prevention of depressive symptoms in the menopause transition: a randomized clinical trial. JAMA Psychiatry. 2018;75(2):149-157. doi:10.1001/jamapsychiatry.2017.3998. Link. Accessed January 18, 2026.

8. Patel K, Allen S, Haque MN, et al. Bupropion: a systematic review and meta-analysis of effectiveness as an antidepressant. Ther Adv Psychopharmacol. 2016;6(2):99-144. doi:10.1177/2045125316629071. Link.

9. National Library of Medicine. DailyMed: Bupropion hydrochloride extended-release tablets (XL) (package insert). Link. Accessed January 18, 2026.

10. StatPearls Publishing. Bupropion. In: StatPearls [Internet]. Link. Accessed January 18, 2026.

11. US Food and Drug Administration. Strattera (atomoxetine hydrochloride) capsules: prescribing information. Link. Accessed January 18, 2026.

12. Dadashova R, Silverstone PH. Off-label use of atomoxetine in adults: is it safe? Ment Illn. 2012;4(2):e19. doi:10.4081/mi.2012.e19. Link: https://pmc.ncbi.nlm.nih.gov/articles/PMC4253379/Accessed January 18, 2026.

13. National Library of Medicine. DailyMed: FETZIMA (levomilnacipran hydrochloride) extended-release capsules (package insert). Link. Accessed January 18, 2026.

14. Tundo A, de Filippis R, Proietti L, et al. Pramipexole augmentation for treatment-resistant unipolar depression. Link. Accessed January 18, 2026.

15. National Library of Medicine. DailyMed: EMSAM (selegiline transdermal system) (package insert). Link. Accessed January 18, 2026.

16. Jessen L, et al. The selegiline transdermal system (Emsam). Link. Accessed January 18, 2026.

17. US Food and Drug Administration. Trintellix (vortioxetine) tablets: prescribing information. Link. Accessed January 18, 2026.

18. Harmer CJ, Duman RS, Cowen PJ. How do antidepressants work? New perspectives for refining future treatment approaches. Lancet Psychiatry. 2017;4(5):409-418. doi:10.1016/S2215-0366(17)30015-9. Link.

19. Sinclair LI, Christmas DM, Hood SD, et al. Antidepressant-induced jitteriness/anxiety syndrome: systematic review. Br J Psychiatry. 2009;194(6):483-490. doi:10.1192/bjp.bp.107.048371. Link.

20. National Library of Medicine. DailyMed: Venlafaxine hydrochloride extended-release capsule (package insert). Link. Accessed January 18, 2026.

21. National Library of Medicine. DailyMed: Duloxetine delayed-release capsule (package insert). Link. Accessed January 18, 2026.

22. National Library of Medicine. DailyMed: EXXUA (gepirone) extended-release tablets (package insert). Link. Accessed January 18, 2026.

23. Wilson TK, Tripp J. Buspirone. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. Link. Accessed January 18, 2026.

24. Gałka N, et al. Gepirone for major depressive disorder. Link. Accessed January 18, 2026.

25. National Library of Medicine. DailyMed: Mirtazapine tablet (package insert). Link. Accessed January 18, 2026.

26. Watanabe N, Omori IM, Nakagawa A, et al. Mirtazapine versus other antidepressive agents for depression. Cochrane Database Syst Rev. 2011;(12):CD006528. doi:10.1002/14651858.CD006528.pub2. Link.

27. National Library of Medicine. DailyMed: Trazodone hydrochloride tablet (package insert). Link. Accessed January 18, 2026.

28. Jaffer KY, Chang T, Vanle B, et al. Trazodone for insomnia: a systematic review. Innov Clin Neurosci. 2017;14(7-8):24-34. Link. Accessed January 18, 2026.

29. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354(12):1243-1252. doi:10.1056/NEJMoa052964. Link.

30. McGrath PJ, Stewart JW, Fava M, et al. Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: a STAR*D report. Am J Psychiatry. 2006;163(9):1531-1541. doi:10.1176/ajp.2006.163.9.1531. Link. Accessed January 18, 2026.

31. US Food and Drug Administration. Drugs@FDA: Abilify (aripiprazole). Link. Accessed January 18, 2026.

32. US Food and Drug Administration. Drugs@FDA: Rexulti (brexpiprazole). Link. Accessed January 18, 2026.

33. National Library of Medicine. DailyMed: AUVELITY (dextromethorphan hydrobromide, bupropion hydrochloride) extended-release tablets (package insert). Link. Accessed January 18, 2026.

34. McCarthy B, et al. Dextromethorphan-bupropion (Auvelity) for the treatment of major depressive disorder. Link. Accessed January 18, 2026.

35. Iosifescu DV, et al. Efficacy and safety of AXS-05 (dextromethorphan-bupropion) in patients with major depressive disorder: a phase 3 randomized clinical trial (GEMINI). Link. Accessed January 18, 2026.

36. Tabuteau H, et al. Effect of AXS-05 (dextromethorphan-bupropion) in major depressive disorder (ASCEND). Link. Accessed January 18, 2026.