Antidepressants that most commonly cause significant tiredness include Trazodone, Mirtazapine, and older Tricyclic Antidepressants (TCAs) like amitriptyline, doxepin, and imipramine, often because they're highly sedating and can disrupt sleep. Some SSRIs, like paroxetine (Paxil), can also cause drowsiness, though TCAs and atypical options are generally more sedating overall, with individual reactions varying. Taking them at bedtime can help manage daytime fatigue.
Selective serotonin reuptake inhibitors (SSRIs) include escitalopram (Lexapro), paroxetine (Paxil), and fluoxetine (Prozac). They can cause sleep problems that lead to daytime fatigue.
Amitriptyline, doxepin, imipramine and trimipramine are more likely to make you sleepy than other tricyclic antidepressants are. Taking these medicines at bedtime may help. Amitriptyline, clomipramine, doxepin, imipramine and trimipramine are more likely to cause weight gain than other tricyclic antidepressants are.
A: The study (Zhou et al., 2023) identified Fluvoxamine, Trazodone, and Mirtazapine as having the highest risk of causing somnolence. Other medications like amitriptyline, duloxetine, escitalopram, paroxetine, and sertraline also showed significantly increased risks.
Among the SSRIs, paroxetine appears to cause the most sedation,46 fluvoxamine the most gastrointestinal upset,47 and fluoxetine the most short-term weight loss and activation (e.g., anxiety and agitation).
Prozac (fluoxetine) and Wellbutrin (bupropion) are examples of “energizing” antidepressants; whereas Paxil (paroxetine) and Celexa (citalopram) tend to be more sedating. Initial choices therefore, should be predicated on how the depression presents—as outlined in #2 above.
Medicines That Can Cause Weakness or Fatigue
Fatigue, drowsiness
Consider these strategies: Take a brief nap during the day. Get some physical activity, such as walking. Avoid driving or operating dangerous machinery until the fatigue passes.
Pay attention to physical side effects such as nausea, dizziness, headaches, or a rapid heartbeat. These can be signs of too much antidepressant in your body. Although some side effects fade over time, others indicate that your system is not tolerating the current dose.
Antidepressants that are known to be best for energy include Prozac (fluoxetine), Zoloft (sertraline), and Wellbutrin (bupropion). Wellbutrin is a fairly new type of antidepressant.
This medicine may cause some people to have a false sense of wellbeing, or to become drowsy, dizzy, or less alert than they are normally. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are drowsy, dizzy, or less alert.
For many people, fatigue improves as their body adjusts to the medication, typically within 4-6 weeks. However, some individuals may experience persistent tiredness throughout their treatment. It's important to note that antidepressant side effects, including fatigue, are highly personalized experiences.
Medically reviewed by Kristianne Hannemann, PharmD. Last updated on Dec 3, 2025. Sertraline can make some people feel sleepy due to its effects on chemicals in the brain, especially in the first days to weeks of treatment. Others experience the opposite problem and develop insomnia instead.
Profound and debilitating fatigue is the most common complaint reported among individuals with autoimmune disease, such as systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, celiac disease, chronic fatigue syndrome, and rheumatoid arthritis.
Overall, citalopram appears to be the best-tolerated SSRI, followed by fluoxetine, sertraline, paroxetine, and fluvoxamine. The latter 2 drugs are associated with the most side effects and the highest discontinuation rates because of side effects in clinical trials.
Wellbutrin (bupropion) is often considered one of the most effective antidepressants for increasing energy and motivation.
For most people, Lexapro-related fatigue begins to improve after 2-4 weeks of consistent treatment. As your brain adapts to the medication, energy levels typically start to normalize, and many people find their fatigue resolves completely by the 6-week mark.
Tricyclic antidepressants
These medications may be particularly helpful for CFS/ME patients. For example, the tricyclic amitriptyline is known to relieve many symptoms, including sleeplessness and low energy levels in CFS/ME.
But, even the newer classes of antidepressants—including SSRIs and SNRIs—often cause fatigue. Some of the major SSRIs that cause fatigue include: Aropax, Brisdelle, Paxil (paroxetine) Celexa (citalopram)
However, at least in short-term treatment, many antidepressants with so-called activating effects (e.g. fluoxetine, venlafaxine) may disrupt sleep, while others with sedative properties (e.g., doxepin, mirtazapine, trazodone) rapidly improve sleep, but may cause problems in long-term treatment due to oversedation.
Fibromyalgia (FMS) and chronic fatigue syndrome (CFS), also called myalgic encephalomyelitis (ME/CFS), are chronic conditions that have similar symptoms. Both cause extreme tiredness, which could cause ME/CSF to be misdiagnosed as fibromyalgia.
Both Prozac and Zoloft are SSRIs that treat depression, anxiety, and related disorders, but Zoloft is FDA-approved for more anxiety-related conditions like PTSD and social anxiety. The key differences are that Prozac lasts longer, but Zoloft has a lower risk for weight gain and is safer for pregnancy.
Both have similar side effects, including nausea, fatigue, and changes in appetite. Lexapro tends to cause more drowsiness, which can help if you have trouble sleeping. Zoloft is more likely to cause stomach issues and sweating but is less sedating during the day.
While Prozac is generally more stimulating than some other antidepressants, it can still lead to feelings of drowsiness or low energy in certain individuals. This Prozac side effect may occur more frequently when you first start taking the medication, as your body adjusts to it.