Wellbutrin (Bupropion) vs SSRIs for Depression

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Bupropion and the SSRIs produce the same response and remission rates in major depression. In a pooled analysis of individual patient data from 7 randomized, double-blind trials (732 patients on bupropion and 731 on fluoxetine, sertraline, or paroxetine), 62% responded and 47% remitted on bupropion, compared with 63% and 47% on the SSRIs; placebo trailed at 51% and 36% (Thase and colleagues, Journal of Clinical Psychiatry, 2005).

Given equal efficacy, the decision rests on everything else: which side effects a person can live with, whether anxiety sits at the center of the depression, whether ADHD is also present, and what has already been tried. Each question has data behind it, laid out below in the order I weigh it in the depression practice.

Bupropion and SSRIs produce the same remission rates in depression

The Thase analysis used original patient-level data from every trial the manufacturer had run against an SSRI, and its authors concluded that the two were equivalently effective, with sexual dysfunction the principal difference between them.

The equivalence extends to people whose first SSRI has already failed. In STAR*D, 727 adults who had not remitted on citalopram, or could not tolerate it, were randomized to switch to sustained-release bupropion, sertraline, or extended-release venlafaxine for up to 14 weeks. Remission on the clinician-rated Hamilton scale was 21.3% with bupropion, 17.6% with sertraline, and 24.8% with venlafaxine, differences that did not reach statistical significance (Rush and colleagues, New England Journal of Medicine, 2006). Roughly one in four remitted after switching, whichever drug they switched to, and tolerability did not differ.

Accordingly, I don't choose bupropion over an SSRI expecting it to work better. I choose it, or avoid it, for the reasons that follow.

Side effects decide the choice more often than efficacy does

Sexual side effects are the largest difference. In the pooled trials, SSRIs produced significantly more sexual side effects than bupropion or placebo, while bupropion produced no more than placebo (Thase and colleagues, 2005). Real-world data point the same way. In a cross-sectional survey of 6,297 adults on antidepressant monotherapy in 1,101 U.S. primary care clinics, sexual dysfunction was reported by 22% to 25% of patients on bupropion and 36% to 43% on SSRIs; among patients without other reasons for it, the odds were 4 to 6 times greater with an SSRI (Clayton and colleagues, Journal of Clinical Psychiatry, 2002). That study was observational, so the magnitudes should be read loosely, though the direction is broadly consistent with the randomized data. Notably, physicians in that survey consistently underestimated the problem, which is why I ask about it directly at every visit.

Fatigue and oversleeping respond better to bupropion. "Why am I still exhausted if the depression is better?" is one of the more common questions I hear from people who have remitted on an SSRI. A pooled analysis of 6 trials (662 patients on bupropion, 655 on an SSRI) found greater improvement in hypersomnia and fatigue with bupropion. Among those who remitted, 20.5% on bupropion still had residual hypersomnia compared with 32.1% on an SSRI, and 19.5% versus 30.2% had residual fatigue (Papakostas and colleagues, Biological Psychiatry, 2006). The authors called the result preliminary, and it likely reflects bupropion's noradrenergic and dopaminergic action. In practice, a depression dominated by sleepiness, low energy, and low motivation is one where I lean toward bupropion.

Weight favors bupropion as well. In a meta-analysis of 116 studies, weight gain was most associated with amitriptyline, mirtazapine, and paroxetine, while some weight loss occurred with bupropion and, in the acute phase only, with fluoxetine (Serretti and Mandelli, Journal of Clinical Psychiatry, 2010). Individual responses vary widely, and weight is tracked at every visit regardless of drug.

Bupropion carries its own burden. In the placebo-controlled trials summarized in the FDA label, dry mouth occurred in 17% of patients on 300 mg per day of sustained-release bupropion versus 7% on placebo, and insomnia in 11% versus 6%. At 400 mg per day, agitation rose to 9% (versus 2%) and insomnia to 16%. Discontinuation because of adverse reactions was 9% at 300 mg against 4% on placebo. The label also states that bupropion can raise blood pressure and directs monitoring.

Seizure risk is dose-dependent and defines who should never take bupropion

Bupropion lowers the seizure threshold, and the FDA label is specific about how much. At doses of sustained-release bupropion up to 300 mg per day, the seizure incidence was approximately 0.1%, or 1 in 1,000 patients; with immediate-release bupropion at 300 to 450 mg per day, it was approximately 0.4% (13 of 3,200 patients). The label further states that the estimated incidence rises almost tenfold between 450 and 600 mg per day, and that risk is reduced when the dose stays at or below 450 mg once daily and titration is gradual. The relationship is dose-dependent in the strict sense, which is why a missed dose is never doubled.

The contraindications follow from that mechanism. Per the label, bupropion must not be used in anyone with a seizure disorder; anyone with a current or prior diagnosis of bulimia or anorexia nervosa, in whom more seizures were observed; anyone abruptly stopping alcohol, benzodiazepines, barbiturates, or antiepileptic drugs; and anyone who has taken an MAOI within 14 days. The eating-disorder contraindication includes remote history, so I ask about adolescent eating disorders before every bupropion prescription, including in adults who haven't thought about it in twenty years. The label also lists conditions that raise risk short of contraindication, among them other medications that lower the seizure threshold, heavy alcohol use, and misuse of stimulants.

Finally, as with every antidepressant, the label directs screening for bipolar disorder before starting, since antidepressants can precipitate mania or hypomania, and bupropion is not approved for bipolar depression. A family history of bipolar disorder or a past episode of elevated mood changes the plan; the bipolar disorder page covers that evaluation.

SSRIs hold a modest edge when anxiety dominates the depression

Anxious depression is the one symptom profile where the two drugs separate on efficacy. In a pooled analysis of 10 randomized trials (2,122 patients), 1,275 met a Hamilton-scale definition of anxious depression. Among them, response rates were 65.4% with SSRIs and 59.4% with bupropion; among patients with low or moderate anxiety, the drugs did not differ (Papakostas and colleagues, Journal of Clinical Psychiatry, 2008). About 17 patients with anxious depression would need an SSRI rather than bupropion to produce one additional responder. The advantage is real and small.

The formal indications tell the rest of the story. The Wellbutrin XL label carries two indications, major depressive disorder and prevention of seasonal affective disorder, while sertraline's label also covers obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, and social anxiety disorder. Bupropion has no FDA approval for any anxiety disorder, and at 300 mg per day the label reports anxiety in 5% of patients versus 3% on placebo.

Accordingly, when depression arrives alongside a diagnosable anxiety disorder, panic attacks, the pervasive worry described on the generalized anxiety page, or social anxiety, I start with an SSRI. Although anxiety that is part of the depressive episode often improves as the depression lifts on bupropion, I watch the first two weeks for activation, and a person who feels wired on 150 mg is unlikely to do better at 300 mg. Where ADHD may be masquerading as anxiety, see ADHD versus anxiety.

Bupropion added to an SSRI is a reasonable second step, with limits

The best evidence for combining the two comes from STAR*D. After a mean of 11.9 weeks on citalopram without remission, 565 adults had sustained-release bupropion added and 286 had buspirone added. Remission on the Hamilton scale was 29.7% with bupropion and 30.1% with buspirone. However, bupropion produced a larger reduction in self-reported symptom scores (25.3% versus 17.1%) and fewer dropouts for intolerance (12.5% versus 20.6%) (Trivedi and colleagues, New England Journal of Medicine, 2006). About three in ten people who had not remitted on an SSRI alone remitted once bupropion was added.

Starting both drugs together from day one is a different question, and the answer was negative. In CO-MED, 665 outpatients with chronic or recurrent major depression were randomized at the first step to escitalopram plus placebo, bupropion plus escitalopram, or venlafaxine plus mirtazapine. At 12 weeks, remission was 38.8%, 38.9%, and 37.7%, and at 7 months the groups still did not differ (Rush and colleagues, American Journal of Psychiatry, 2011). Neither combination outperformed a single SSRI.

Read together, the two trials support a stepwise approach. I start with one medication, usually paired with psychotherapy, since the combination outperforms either alone for most adults. If the response is partial after an adequate trial, adding bupropion is one of the first moves I consider, and it rises to the top when the residual symptoms are fatigue, low motivation, or SSRI sexual side effects. The combination requires attention to blood pressure and sleep, and it sits within the longer sequence described on the treatment-resistant depression page. Which step comes when is the core work of medication management, decided with the prescriber visit by visit.

Bupropion for adult ADHD is off-label, and the effect is modest

Many people arrive here with both depression and attention problems, having read that Wellbutrin treats both. The evidence is thinner than the internet suggests. A 2017 Cochrane review identified 6 randomized placebo-controlled trials in adults with ADHD, 438 participants in all, using long-acting bupropion at 150 to 450 mg daily for 6 to 10 weeks. Bupropion reduced ADHD symptom severity with a standardized mean difference of -0.50 (95% CI -0.86 to -0.15; 3 studies, 129 participants) and increased the proportion with clinical improvement by half (risk ratio 1.50; 4 studies, 315 participants). Withdrawals for adverse effects matched placebo. The authors rated the evidence low quality, because of risk of bias and small samples, and wrote that further research is very likely to change the estimates (Verbeeck and colleagues, Cochrane Database of Systematic Reviews, 2017).

A standardized mean difference of 0.50 is a medium effect by the usual conventions, from trials that mostly excluded people with psychiatric comorbidity, which is to say they excluded the depressed adults most likely to be prescribed it for this purpose. Stimulants remain first-line for adult ADHD; the options are laid out on the ADHD medication guide and the non-stimulant ADHD medication page. Where bupropion earns a place is the adult with both conditions who wants one medication before two, or who cannot take a stimulant. If the depression lifts and attention problems remain, a stimulant can be added, with the caution that the label lists stimulant misuse among the factors that raise seizure risk. Sorting out which problem is which is the subject of depression versus ADHD.

How the FDA label doses Wellbutrin XL, and how I use it

The Wellbutrin XL label directs a starting dose of 150 mg once daily in the morning, which may be increased to the target dose of 300 mg once daily after 4 days. When stopping treatment at 300 mg, the label describes a step down to 150 mg before discontinuing rather than an abrupt halt. The trials cited above used the sustained-release form at up to 400 mg per day, which the label describes as similar in bioavailability to XL.

In my own practice, I start at 150 mg and usually hold there for a week or two before moving to 300 mg, longer than the label's 4 days, because early insomnia and jitteriness are the main reasons people quit, and both tend to settle. I check blood pressure at baseline and after each increase, and I ask about seizures, head injury, eating disorders, alcohol, and every other medication before the first prescription. The dose that works is individual, and the decision is made with the prescriber, never by adjusting on one's own.

Who this practice fits, and when to go elsewhere

This practice fits adults and adolescents in Manhattan who want a deliberate choice between antidepressants, people on an SSRI who are left with sexual side effects, fatigue, or weight gain, and adults with both depression and ADHD who need both evaluated together. It also fits people started on bupropion elsewhere who haven't improved and want a second opinion. If you're unsure whether a psychiatrist is the right starting point, this page sorts out who treats depression.

Some situations belong elsewhere first. Anyone with a seizure disorder or an active eating disorder should have that condition managed, and bupropion is off the table in either case. Someone stopping heavy alcohol or benzodiazepine use needs supervised withdrawal first. An active suicidal crisis needs an emergency department today; the callout below gives the numbers.

Cost and booking

Initial evaluations run 60 to 90 minutes, which is the time it takes to go through the history above, including prior medication trials with doses and durations. The practice is out-of-network with all insurance plans. You pay directly and receive a superbill to submit for reimbursement; many NYC plans with out-of-network benefits reimburse a meaningful share once the deductible is met. The numbers are laid out at fees and out-of-network costs, and this page explains how to check your own benefits before the first visit.

Bring a list of every antidepressant you have taken, with doses and durations. Schedule a consultation or call (646) 893-4309.

Related

Depression · Medication management · Treatment-resistant depression · Medication vs therapy vs both · ADHD medications · Non-stimulant ADHD medication · Generalized anxiety disorder · Second opinions · Emotional blunting on antidepressants · Antidepressant sexual side effects · Antidepressants and weight gain · Depression with ADHD: combining medications · Anxiety medication options · How long antidepressants take to work · Lexapro vs Zoloft · SSRIs for teens · Stopping antidepressants

When Depression Becomes an Emergency

Every antidepressant label, bupropion's included, carries a boxed warning about increased suicidal thinking and behavior in children, adolescents, and young adults, and the weeks after starting or changing a dose are the time to watch most closely. Suicidal thoughts short of a crisis warrant same-day or next-day psychiatric evaluation.

Frequently Asked Questions

Is Wellbutrin as effective as an SSRI for depression?

Yes. In a pooled analysis of 7 randomized, double-blind trials, 47% of patients remitted on bupropion and 47% on an SSRI (fluoxetine, sertraline, or paroxetine), with response rates of 62% and 63%. In STAR*D, people who switched from citalopram to bupropion, sertraline, or venlafaxine remitted at similar rates. The differences lie in side effects and in specific symptom profiles.

Does Wellbutrin cause sexual side effects?

Rarely more than placebo. In the pooled trials, SSRIs produced significantly more sexual side effects than bupropion or placebo, while bupropion produced no more than placebo. In a survey of 6,297 adults on antidepressant monotherapy, sexual dysfunction was reported by 22% to 25% on bupropion and 36% to 43% on SSRIs. Switching to or adding bupropion is a common response to SSRI sexual side effects.

Does Wellbutrin help with anxiety?

It helps anxiety that is part of a depressive episode, though less reliably than an SSRI. In a pooled analysis of 10 trials, people with anxious depression responded to SSRIs 65.4% of the time and to bupropion 59.4% of the time, a difference of 6 percentage points. Bupropion has no FDA approval for any anxiety disorder and can itself cause anxiety, agitation, and insomnia. For panic disorder, generalized anxiety, or social anxiety, I start with an SSRI.

Can Wellbutrin be taken with an SSRI?

Yes, and it is one of the better-studied combinations. In STAR*D, adding sustained-release bupropion to citalopram after an incomplete response remitted 29.7% of patients, with fewer dropouts for intolerance than adding buspirone. Starting both together from day one did not help: in CO-MED, bupropion plus escitalopram remitted 38.9% at 12 weeks, the same as escitalopram alone. The combination is for partial responders.

Does Wellbutrin work for adult ADHD?

Modestly, and off-label. A 2017 Cochrane review of 6 randomized trials (438 adults) found bupropion reduced ADHD symptom severity with a standardized mean difference of -0.50 and increased the chance of clinical improvement by half (risk ratio 1.50), on evidence the authors rated low quality. Stimulants remain first-line. Bupropion fits adults who have both depression and ADHD, or who cannot take a stimulant.

Who should not take Wellbutrin?

The FDA label contraindicates bupropion in anyone with a seizure disorder, a current or prior diagnosis of bulimia or anorexia nervosa, abrupt withdrawal from alcohol, benzodiazepines, barbiturates, or antiepileptic drugs, or use of an MAOI within 14 days. Seizure risk is dose-related: about 0.1% at doses up to 300 mg per day and about 0.4% at 300 to 450 mg per day. Uncontrolled high blood pressure and a history of mania also call for caution.

Sources

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2. Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. 2006;354(12):1231–1242. PMID 16554525
3. 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. PMID 16554526
4. Rush AJ, Trivedi MH, Stewart JW, et al. Combining medications to enhance depression outcomes (CO-MED): acute and long-term outcomes of a single-blind randomized study. Am J Psychiatry. 2011;168(7):689–701. PMID 21536692
5. Papakostas GI, Stahl SM, Krishen A, et al. Efficacy of bupropion and the selective serotonin reuptake inhibitors in the treatment of major depressive disorder with high levels of anxiety (anxious depression): a pooled analysis of 10 studies. J Clin Psychiatry. 2008;69(8):1287–1292. PMID 18605812
6. Papakostas GI, Nutt DJ, Hallett LA, Tucker VL, Krishen A, Fava M. Resolution of sleepiness and fatigue in major depressive disorder: a comparison of bupropion and the selective serotonin reuptake inhibitors. Biol Psychiatry. 2006;60(12):1350–1355. PMID 16934768
7. Clayton AH, Pradko JF, Croft HA, et al. Prevalence of sexual dysfunction among newer antidepressants. J Clin Psychiatry. 2002;63(4):357–366. PMID 12000211
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9. Verbeeck W, Bekkering GE, Van den Noortgate W, Kramers C. Bupropion for attention deficit hyperactivity disorder (ADHD) in adults. Cochrane Database Syst Rev. 2017;10:CD009504. PMID 28965364
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11. U.S. Food and Drug Administration. Zoloft (sertraline hydrochloride) prescribing information. Revised 2023. accessdata.fda.gov