Is there anything different about the brains of people with obsessive-compulsive disorder (OCD) that is responsible for their overwhelming intrusive thoughts and resulting compulsions? It’s not uncommon to find articles or advertisements suggesting that it may be caused by a “chemical imbalance.” But what exactly does this mean, and how good is the evidence for it?
We spoke to Dr. Jamie Feusner, Chief Medical Officer at NOCD, to better understand the chemical imbalance theory of mental illness, assess the evidence for it with respect to OCD, and analyze competing theories. Here’s what we learned.
What is the chemical imbalance theory of mental illness?
Our brains are made up of billions of neurons which rely on chemical messengers called neurotransmitters to communicate with each other. These chemical messengers float around in an area between neurons called the synapse, where they are released from some neurons and can bind to receptors on other neurons. Here they have either an inhibitory or excitatory effect, meaning they can decrease or increase the odds that the neuron will “fire,” sending electrical signals to other brain areas where more chemical messengers are released to other neurons.
Simply stated, the chemical imbalance theory of mental illness claims that mental health conditions are caused and sustained by too much or too little of a certain neurotransmitter or set of neurotransmitters. For example, some have argued that low amounts of serotonin and norepinephrine contribute to depression. Similarly, others suggest that an overabundance of dopamine is central to conditions of schizophrenia and psychosis.
What led researchers to suspect that mental health conditions might be impacted by chemical imbalances? “The chemical imbalance theory didn’t actually come from the direct study of the brain,” says Dr. Feusner. The story is actually quite interesting:
“Instead, what happened was that some people who received antibiotics for tuberculosis
in the 1950s called iproniazid were observed to have elevations in their mood, were more active, and had better appetite and sleep. One of this medication’s mechanisms was that it increased levels of the neurotransmitters serotonin, norepinephrine, and dopamine in the synapses between neurons. It was later tested as a medication to treat depression, and found to have efficacy. Also in the 1950s, researchers and clinicians observed that a blood pressure medication called reserpine that reduced serotonin, norepinephrine, and dopamine in the brain, caused depression in some people. These findings led to the ‘monoamine hypothesis of depression.’ Based on this, researchers developed and tested new medications that increased synaptic levels of serotonin, norepinephrine, and/or dopamine and found that many worked to treat depression. Later, ones that more specifically targeted serotonin were developed—selective serotonin reuptake inhibitors (SSRIs)—which were also effective and tended to cause fewer side effects than the more nonspecific ones. From this came the “serotonin hypothesis” of depression. In the 1990s and early 2000s, pharmaceutical companies began communicating the idea that depression was the result of an “imbalance” or deficiency of brain serotonin. This idea was spread through popular books and websites. However, this hypothesis was only based on indirect evidence—that medications that increase synaptic levels of serotonin improve depression. A similar serotonin hypothesis of OCD developed, starting with the same indirect evidence from the antidepressants clomipramine and SSRIs improving OCD symptoms in many. More recently, there has been a glutamate hypothesis of OCD.”
Meanwhile, researchers studied the brain to look for chemical imbalances more directly. For example, they examined concentrations of various neurotransmitters in the blood or brains of people with mental health conditions. The results of these studies were mixed. “There’s no consistent finding of a deficiency in any neurotransmitter system for OCD,” says Dr. Feusner. “Some studies have found evidence for abnormal break-down products of serotonin or have found abnormal glutamate levels in the brain while others haven’t, and nothing has emerged conclusively to support it.” A 2022 review of the history and research on the chemical imbalance theory came to this conclusion regarding depression. The authors state the “results remain inconsistent and overall there is no convincing evidence of serotonin system abnormalities in people with depression.”
However, a lack of consistent evidence does not necessarily mean the theory is entirely false. Dr. Feusner explains how this is possible. He suggests that one hypothetical possibility is that abnormalities in neurotransmitter systems are part of the problem but not the main problem or the primary type of dysfunction that causes the symptoms of OCD. Another possibility is OCD has different neurobiological and/or environmental causes or contributors in different people. “It may be that some subsets of people with OCD do have abnormalities in the glutamate system, for example, and other people might have abnormalities in the serotonin system. But because the field tends to study them all together and average the results, it could all wash out, which might explain why we don’t get a consistent signal.”
Ultimately, he proposes a more balanced perspective about neurotransmitter system abnormalities. “I wouldn’t say it’s been debunked, really. We’ve just learned that it’s much more complex than a simple chemical imbalance. Our brains are not like a stew, where if you don’t have 40% glutamate levels, then you’re going to have OCD.”
Are antidepressants still effective?
If antidepressants have the effect of increasing the levels of certain neurotransmitters, but the support for the chemical imbalance theory of mental health conditions is inconsistent, does that mean that these medications aren’t actually effective?
It absolutely does not mean this. After all, the chemical imbalance theory was formed after scientists noticed that certain medications happened to improve depression and also increase the levels of neurotransmitters like serotonin. Moreover, studies on the efficacy of antidepressants like SSRIs for OCD have consistently found them effective. So whether or not the chemical imbalance theory is correct, antidepressants do work.
One might wonder, though, how medications that target neurotransmitters work if the chemical imbalance theory remains so uncertain. Dr. Feusner has a helpful analogy to explain how this is possible.
“Let’s say your car was getting worse gas mileage over time. The real cause is that your tires were going flat. You might still be able to improve your gas mileage without inflating your tires by using better gas, not turning on the air conditioning, or being more mindful of how hard you accelerate. All of this might work even though the root of the problem is low tire pressure.”
Something similar may be going on with antidepressants that alter the balance of chemicals in our brains. “You can give it different gas in the form of medications that affect neurotransmitters to compensate for some other issue, but it may not solve the underlying problem,” Dr. Feusner states. “So, rather than correcting an abnormality, antidepressants are better seen as tools to improve symptoms.”
None of this is to say that antidepressants are a bad solution. Many medications are necessary and appropriately used despite not necessarily fixing underlying problems. For example, acetaminophen (Tylenol) can reduce pain and fever when someone has the flu, even though it’s not affecting the virus that caused it or correcting for a specific deficiency. Medications don’t need to get at the heart of the issue to be effective.
An alternative theory
When it comes to the neurological basis of OCD and other mental health conditions, the chemical imbalance theory isn’t the only promising explanation.
Circuits theory of OCD
A compelling alternative to the chemical imbalance theory of mental illness states that abnormal activity in specific neural circuits, or populations of neurons and brain regions that are interconnected and serve certain functions, neurobiologically contributes to OCD symptoms and/or possibly causes OCD. “In OCD, there are very well-defined circuits that many studies have all shown to be abnormally active,” says Dr. Feusner. “These circuits are involved in things like habit-formation and determining our physical and mental reactions to salient stimuli in the environment.”
The theory has been around for several decades. In that time, researchers have identified several brain regions and circuits that may be implicated in OCD. In particular. Dr. Feusner notes that “these circuits involve regions like the anterior cingulate cortex, orbitofrontal cortex, caudate, putamen, thalamus, the Globus pallidus, and other areas. In the past couple of decades we’ve learned that the picture is more complex, and that other brain networks in addition to these circuits are linked to OCD and OCD symptoms.”
Research has found that traditional medications like SSRIs reduce hyperactivity in circuits involving these regions. Newer non-invasive interventions, such as transcranial magnetic stimulation (TMS), may work on these circuits as well. Importantly, experiments have demonstrated that non-medical treatments, like exposure and response prevention (ERP) therapy, the gold standard for treating OCD, can reduce hyperactivation in the circuits associated with OCD.
Neurobiological factors, including genetics, are not the only factors that determine whether one develops OCD or that impact the severity of their symptoms. How and when OCD manifests depends on several factors and involves complex interactions with a variety of variables, including:
- Stress level: Stress and trauma can make one more disposed to developing OCD.
- Age: OCD frequently begins in adolescence or early adulthood when one is experiencing major development and life changes.
- Substance use: Studies have shown that some drugs, such as stimulants, may contribute to OCD.
- Infectious illnesses and the body’s responses to them: OCD is sometimes associated with some illnesses, many of which are more common in childhood, such as Lyme disease or strep throat. This can lead to a sudden onset of OCD symptoms.
- Perinatal complications: Lower birth weight, use of forceps in delivery, and protracted labor have been associated with increased risk of development of OCD.
Much of this evidence comes from association and is not necessarily causal. In addition, no single factor will lead to OCD in most people, and single genes do not lead to OCD. They have to occur in the proper context, alongside other factors, and the necessary combinations are likely different for different people.