Otezla (apremilast) can cause depression because it works by blocking an enzyme called PDE4, which plays a role not just in inflammation but also in brain signaling pathways that regulate mood. In clinical trials for plaque psoriasis, 1.3% of patients on Otezla reported depression compared to 0.4% on placebo. The risk is real but relatively small, and the FDA includes a specific warning about depression on the drug’s label.
How PDE4 Inhibition Affects the Brain
Otezla treats psoriasis, psoriatic arthritis, and Behçet’s disease by blocking PDE4, a family of enzymes that break down a signaling molecule called cAMP. When PDE4 is blocked, cAMP levels rise inside cells, which dials down the inflammatory response. That’s the therapeutic benefit. The problem is that PDE4 enzymes aren’t only found in immune cells. They’re also active in the brain, where cAMP is involved in regulating neurotransmitters.
Animal research has shown that apremilast alters GABA signaling in the central amygdala, a brain region involved in emotional processing and anxiety. Specifically, it increases GABA release through a cAMP-dependent pathway. GABA is the brain’s primary inhibitory neurotransmitter, meaning it dampens neural activity. Shifting this balance in mood-regulating brain areas could plausibly contribute to depressive symptoms in some people, though the exact chain of events in humans isn’t fully mapped out. PDE4 exists in four subtypes (A, B, C, and D), and Otezla inhibits all of them rather than targeting a single one, which means its effects in the brain are broad rather than precise.
What the Clinical Trial Numbers Show
The FDA prescribing information breaks down depression rates by condition. In psoriatic arthritis trials, 1.0% of patients on Otezla reported depression or depressed mood during the first 16 weeks, compared to 0.8% on placebo. That’s a narrow gap. In plaque psoriasis trials, the difference was more pronounced: 1.3% on Otezla versus 0.4% on placebo, roughly three times the rate.
Serious depression was uncommon. In psoriatic arthritis trials, 0.2% of Otezla-treated patients had depression classified as serious. In psoriasis trials, that figure was 0.1%. Suicidal thoughts or behavior occurred in 0.1% to 0.2% of patients on Otezla across the different trials. For context, in the psoriatic arthritis trials, two patients on placebo died by suicide while none on Otezla did, illustrating that the underlying conditions themselves carry meaningful psychiatric risk.
Long-term safety data from the ESTEEM psoriasis trials, following patients for three or more years, found that the rate of depression held steady at 1.8 per 100 patient-years over time. It did not climb with continued use, suggesting the risk doesn’t compound the longer you take the drug.
Who Faces Higher Risk
Depression, suicidal thoughts, and suicidal behavior are more common in people with psoriasis and psoriatic arthritis than in the general population, even without Otezla in the picture. Chronic skin disease takes a well-documented toll on mental health. This makes it harder to tease apart how much of the depression seen in Otezla patients comes from the drug itself versus the condition it’s treating.
That said, post-marketing reports collected by both the FDA and the UK’s medicines regulator have documented suicidal thoughts and behavior in patients taking Otezla who had no prior history of depression. This is significant because it suggests the drug can trigger mood changes even in people who wouldn’t otherwise be considered psychiatrically vulnerable. Patients already dealing with depression or other psychiatric symptoms, or those taking other medications that affect mood, are flagged as needing especially careful evaluation before starting treatment.
What Mood Changes Can Look Like
The FDA label doesn’t specify a precise timeline for when depression tends to emerge. In clinical trials, mood-related side effects were tracked during the first 16 weeks and then through longer follow-up periods, but no single window is identified as the highest-risk phase. This means mood changes could develop early in treatment or after months on the drug.
The symptoms to watch for include new or worsening feelings of sadness, hopelessness, or low motivation, as well as changes in sleep, appetite, or interest in activities you normally enjoy. More concerning signs include thoughts of self-harm or suicide. In clinical trials, 0.3% of psoriatic arthritis patients on Otezla stopped treatment because of depression, compared to none on placebo. Most patients who experienced mood changes did not need to discontinue, but some did.
Monitoring While on Otezla
The FDA recommends that you, your family members, and caregivers stay alert for new or worsening mood symptoms throughout treatment. This isn’t a side effect that only matters in the first few weeks. If you notice a shift in your emotional baseline, that information is worth bringing to your prescriber promptly so they can reassess whether the benefits of staying on Otezla still outweigh the risks for you specifically.
If you have a history of depression or suicidal thinking, that doesn’t automatically rule out Otezla, but it does mean the decision to start treatment should involve a frank conversation about your psychiatric history. The UK’s Medicines and Healthcare Products Regulatory Agency issued a direct communication to healthcare professionals emphasizing this point, noting that the balance of benefits and risks needs individual assessment for anyone with prior psychiatric symptoms or anyone already taking medications that can affect mood.