When people think of medication for depression, they usually think of SSRIs like sertraline or escitalopram, or SNRIs like venlafaxine or duloxetine. These are the workhorses of antidepressant treatment, and for many people they work well. But they don’t work for everyone, and when they don’t, the question becomes: what else is out there?
More than most people realize.
Augmentation strategies
Sometimes the answer isn’t replacing your antidepressant but adding something alongside it. This is called augmentation, and it’s one of the most common next steps when a single antidepressant isn’t getting the job done.
Atypical antipsychotics. Medications like aripiprazole or brexpiprazole are FDA-approved as add-ons to antidepressants for depression. Despite the name, they’re not being used to treat psychosis here. They work on different receptor systems and can boost the effectiveness of the antidepressant you’re already on.
Lithium. More commonly associated with bipolar disorder, lithium has solid evidence as an augmentation agent for unipolar depression that hasn’t responded to antidepressants alone.
Thyroid hormone. Low-dose thyroid supplementation (T3) has been used as an augmentation strategy for decades, particularly in cases where standard options fall short.
Different classes of antidepressants
If SSRIs and SNRIs haven’t worked, there are other classes worth considering:
Bupropion. Works on dopamine and norepinephrine rather than serotonin. Often used when SSRIs cause fatigue, weight gain, or sexual side effects, or when ADHD symptoms coexist with depression.
Mirtazapine. Works through a different mechanism than SSRIs and can be particularly helpful when insomnia and appetite loss are prominent symptoms.
Tricyclic antidepressants (TCAs). Older medications like nortriptyline still have a role, especially when newer options haven’t worked. They require more monitoring but can be effective for some people.
MAOIs. Monoamine oxidase inhibitors like tranylcypromine are among the most effective antidepressants available, but dietary restrictions and drug interactions make them harder to use. They’re typically reserved for cases where other options have been exhausted.
Newer treatment approaches
The last several years have brought genuinely new options for people with treatment-resistant depression:
Esketamine (Spravato). An FDA-approved nasal spray for treatment-resistant depression, administered in a clinical setting. It works through glutamate pathways rather than serotonin, which is why it can help people who haven’t responded to conventional antidepressants.
Ketamine infusions. IV ketamine is used off-label for depression at some clinics. It works through a similar mechanism as esketamine and can provide rapid symptom relief, though insurance coverage varies.
Therapy as a treatment, not just support
If you’ve been on medication but haven’t engaged in structured therapy, that’s a gap worth addressing. Specific therapy approaches have strong evidence for depression on their own, and even stronger evidence when combined with medication:
- CBT (Cognitive Behavioral Therapy) helps restructure thought patterns that maintain depression
- Behavioral Activation focuses on re-engaging with activities and breaking the withdrawal cycle
- EMDR can be effective when trauma is fueling the depression
The point isn’t to try everything at once
The point is that there’s a sequence of options, and most people with treatment-resistant depression haven’t actually tried all of them. A good psychiatrist will work through these systematically based on your history, your symptoms, and what’s already been attempted.
If you’ve been on one or two antidepressants and felt like nothing works, you’ve only scratched the surface. We work with patients across this full range of options at our Toledo, Monroe, and Perrysburg locations. Let’s figure out what’s next.