What Causes Depression? What the Science Shows Beyond the Chemical Imbalance

When you’re depressed, “why” can feel like the loudest question in the room. Maybe you’ve wondered whether you caused it, whether it’s in your genes, or whether something in your brain is simply broken. It’s okay to not have all the answers right now, and you deserve a better one than “chemical imbalance.”

Your brain is constantly adapting to what happens to you, through networks of nerve cells that strengthen or weaken with experience, stress hormones that rise and fall, and an immune system that signals to the brain. Depression seems to emerge when several of those systems are pushed off balance, which is why NIMH’s depression overview says genetic, biological, environmental, and psychological factors all play a role. Understanding your own mix takes precision, because two people with the same diagnosis can arrive there by very different routes.

For decades, the standard explanation was the serotonin hypothesis, the idea that depression comes from too little serotonin and that antidepressants work by topping it up. It shaped how a generation understood depression, and the medications developed during that era do work. In a 2018 Lancet meta-analysis of 522 trials, all 21 antidepressants studied outperformed placebo for major depression. The results are real, and the science is well established.

But low serotonin is no longer the best explanation for why depression happens, and at Siggy we’d rather give you the current picture than a slogan.

That picture is a multi-factor model, in which inherited risk, early experiences, ongoing stress, inflammation, sleep, and activity add up over time. It explains the same illness the serotonin hypothesis tried to explain, with more precision, because it accounts for why depression runs in families and also often follows hard life events. A 2022 umbrella review found no consistent evidence that depression is caused by lowered serotonin. That shift comes from the research itself, and it changes how prevention and treatment are framed.

What This Page Covers

• Is Depression Caused by a Chemical Imbalance?
• Is Depression Genetic?
• How Do Stress and Childhood Adversity Raise Risk?
• What Is Happening in the Brain and Body?
• Can Sleep, Activity, and Health Conditions Contribute?
• What Does This Mean for Treatment?
• How Siggy Fits In
• The Bottom Line on What Causes Depression
• Start Your Anonymous Intake

Is Depression Caused by a Chemical Imbalance?

The short answer is that it’s more complicated than that. The 2022 umbrella review pulled together 17 major studies across the main areas of serotonin research. Studies of serotonin and its breakdown products in body fluids showed no association with depression, and the two largest, highest-quality genetic studies of the serotonin transporter gene, with more than 115,000 and 43,000 participants, found no link to depression.

That doesn’t mean brain chemistry is irrelevant, or that antidepressants are a placebo. The 2018 meta-analysis above still found that antidepressants outperform placebo. It does mean the old explanation was too simple. Many chemical messengers, brain circuits, and body systems appear to be involved, working together rather than one being “low.”

Is Depression Genetic?

Genes play a real but partial role. A 2000 twin meta-analysis estimated that about 37% of the risk for major depression is heritable, and family studies found that close relatives of people with depression had 2.84 times the odds of having it themselves. The same analysis attributed most of the remaining risk to factors unique to each person, along with measurement error.

The genetic picture is also spread across many genes. A 2025 genome-wide study of 688,808 people with major depression and more than 4.3 million controls from 29 countries identified 697 genetic associations at 635 locations in the genome. Even combined into a single score, those variants explained only up to 5.8% of the variation in depression risk among people of European ancestry. In practice, that means no single gene causes depression, and a family history raises your odds without deciding your future.

How Do Stress and Childhood Adversity Raise Risk?

Hard experiences, especially early ones, leave a mark. The WHO fact sheet notes that people who have lived through abuse, severe losses, or other stressful events are more likely to develop depression.

Childhood maltreatment stands out in the research. A 2017 maltreatment meta-analysis of 184 studies found that nearly half of patients with depression reported a history of childhood maltreatment. People who were maltreated were 2.66 to 3.73 times more likely to develop depression as adults, tended to develop it earlier, and were twice as likely to have depression that was chronic or hard to treat. Emotional abuse and neglect were most strongly linked to severity. If that’s part of your story, it isn’t a personal failing, and it’s worth telling a clinician. Our guide to childhood trauma and adult mental health goes deeper.

What Is Happening in the Brain and Body?

Researchers have found differences in both the body and the brain, though sorting out cause from effect is still a work in progress.

Inflammation is one thread. A 2019 inflammation meta-analysis of 30 studies found that about 27% of people with depression had low-grade inflammation, measured by a blood marker called C-reactive protein, and over half had mildly elevated levels. That suggests inflammation may be relevant for a meaningful subgroup, though not for everyone.

Brain structure is another. In the ENIGMA imaging study of 1,728 people with major depression and 7,199 controls, people with depression had slightly smaller hippocampal volumes, about 1.24% on average. The hippocampus helps regulate memory and stress. The difference was driven by people with recurrent depression and was most pronounced when depression began by age 21, while people in their first episode showed no difference. That pattern is consistent with repeated episodes affecting the brain, though a study like this can’t show which came first.

Can Sleep, Activity, and Health Conditions Contribute?

Everyday factors matter too, and some of the strongest evidence points to sleep and movement.

A 2011 insomnia meta-analysis of 21 long-term studies found that people without depression who had insomnia were about twice as likely to develop depression later as people who slept well. Physical activity seems to work in the other direction. A genetic causal analysis using data from more than 600,000 adults found that higher activity measured by wearable sensors was linked to a lower risk of major depression, with 26% lower odds for each standard deviation increase. Self-reported activity didn’t show the same link, which suggests the measured kind is what counts.

Medical issues can also produce depressive symptoms. A StatPearls clinical review lists thyroid and other hormone disorders, vitamin B12 or D deficiency, neurological conditions, and some medications, including steroids, among possible causes. That’s why a good evaluation looks beyond mood.

Here’s how the main factors compare at a glance.

Factor	What the Research Shows	Type of Evidence
Family genetics	About 37% of risk is heritable	Twin and family studies
Childhood maltreatment	2.66 to 3.73 times higher risk	Meta-analysis of 184 studies
Insomnia	About twice the risk of later depression	Meta-analysis of 21 studies
Physical activity	Measured activity linked to lower risk	Genetic causal analysis
Inflammation	Low-grade inflammation in about 27%	Meta-analysis of 30 studies
Low serotonin	No consistent evidence	Umbrella review of 17 studies

What Does This Mean for Treatment?

If depression has several contributors, it makes sense that treatment often works on several at once. Medication, therapy, sleep, and physical activity each target a different piece, and combining approaches is common. Our guide to major depressive disorder walks through what the evidence shows for each option and how progress is measured over time.

Knowing your contributors can also help you spot patterns. If poor sleep or a stressful stretch at work tends to come before a dip in mood, that’s useful information for you and your clinician. And if you can’t point to any cause at all, that’s common too. You don’t need a clear reason to deserve care.

How Siggy Fits In

Siggy’s licensed prescribers diagnose and treat the full range of mental health conditions, including depression. The intake asks about the things that shape depression risk, like sleep, stress, family history, health conditions, and past treatments, so a licensed prescriber can see your full picture before anything is prescribed.

The anonymous intake asks for no name, email, or account, which can make it easier to share things like childhood experiences or drinking honestly. You’ll get a downloadable summary to keep or share with any clinician. If you’re already being treated for depression, keep working with the clinician who manages it, and bring your summary along.

Siggy isn’t an emergency service. If you’re in crisis, call 911 or call or text 988. This article is for education only and isn’t a substitute for personal medical advice. It reflects sources available as of October 2026.

The Bottom Line on What Causes Depression

Depression isn’t caused by one missing chemical, one gene, or one bad decision. It usually reflects a mix of inherited risk, early experiences, ongoing stress, inflammation, sleep, activity, and health, and that mix differs from person to person. The upside of that complexity is that there are many places to intervene. If you’re trying to make sense of your own low mood, our explainer on why you might feel depressed is a good next read.

Start Your Anonymous Intake

If you’re in crisis right now, call 911 or call or text 988 first. If you’ve been feeling low and want help understanding what’s driving it and what might help, start your anonymous intake. It’s free, there’s no name or email required, and a licensed prescriber reviews your intake before anything is prescribed. Your summary is yours to keep and share with whoever helps you next.