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Why Don't Antidepressants Work for Everyone?
Have you ever tried multiple antidepressants with little relief, or found that instead of feeling better, you became more anxious, irritable, or emotionally flat? Many people carry quiet shame when medications do not work as expected, wondering whether they are somehow resistant to treatment or failing to try hard enough. According to Dr. J Dunn, the answer is far more nuanced and far less personal than most people realise.
The reality is that we are biochemically and genetically different. Those differences shape how our brains produce, regulate, and clear neurotransmitters such as serotonin and dopamine. When prescribing does not take those differences into account, treatment can feel like an exhausting cycle of trial and error rather than a carefully matched intervention.
This conversation is not about rejecting medication. For individuals in acute crisis, antidepressants can be life-saving and essential. The deeper question is how we can move from broad assumptions toward precision, so that support is aligned with the way an individual’s brain and body actually function.
Moving Beyond the “Chemical Imbalance” Narrative
For decades, depression has often been described as the result of a simple chemical imbalance, typically framed as low serotonin. While this explanation helped reduce stigma at a time when mental health was poorly understood, it oversimplifies a highly intricate biological system.
Neurotransmitters do not simply exist in isolation at fixed levels. The body must:
- Synthesise them from precursor nutrients
- Convert them through multiple enzymatic steps
- Use them at receptor sites
- Break them down into metabolites
- Clear them efficiently from the system
Each of these steps is influenced by enzymes, and the efficiency of those enzymes is often shaped by genetic variants. When one part of the pathway functions differently, the entire system can behave differently.
Understanding depression through this broader biochemical lens helps explain why a single medication strategy does not produce the same outcome for everyone.
How Serotonin and Dopamine Are Made
Two of the most studied neurotransmitters in mood regulation are serotonin and dopamine.
Serotonin is synthesised from the amino acid tryptophan, which is converted into 5-hydroxytryptophan (5-HTP) and then into serotonin. Dopamine begins with the amino acid tyrosine, which is converted into L-DOPA and then into dopamine. Dopamine can subsequently be converted into norepinephrine and adrenaline.
If genetic variants affect any enzyme along these pathways, the brain may not produce optimal amounts of these neurotransmitters. In such cases, a person may experience symptoms associated with low serotonin or dopamine, including low mood, reduced motivation, or difficulty with focus.
However, production is only one part of the equation.
The Often Overlooked Breakdown Pathways
Many antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), function by increasing the availability of serotonin in the brain. For some individuals, this mechanism provides significant relief. For others, it produces uncomfortable or even distressing side effects.
If someone has a genetic variant that impairs the breakdown of serotonin, increasing serotonin levels further may lead to overstimulation rather than balance. Symptoms can include irritability, anxiety, insomnia, agitation, or emotional blunting. In these cases, the medication is not inherently harmful; it is simply mismatched to that person’s biochemical pattern.
A similar principle applies to dopamine-enhancing medications. If dopamine is not cleared efficiently, boosting its production can intensify anxiety, restlessness, or symptoms resembling attention-deficit patterns. The issue is not personal weakness or psychological resistance; it is the interaction between medication and an individual’s metabolic capacity.
Detoxification pathways also play a role. Genetic differences in how the body processes and eliminates medications can result in drugs feeling either overwhelmingly strong or strangely ineffective. Without understanding these pathways, prescribing can become a guessing process rather than a precise intervention.
MAO Inhibitors and Enzyme Sensitivity
Monoamine oxidase inhibitors (MAOIs) represent another example of why genetic context matters. These medications work by inhibiting the enzyme monoamine oxidase, which is responsible for breaking down neurotransmitters such as serotonin and dopamine.
If a person already carries a genetic variant that reduces the activity of this enzyme, further inhibition can create an excessive buildup of neurotransmitters. This can increase the risk of agitation, instability, or other adverse effects. Precision prescribing aims to identify such vulnerabilities before medication is introduced, rather than discovering them through uncomfortable reactions.
Why Anxiety and Insomnia Can Increase
One of the most confusing experiences for patients is feeling more anxious or wired after starting an antidepressant that was intended to calm depressive symptoms. Biochemically, this can occur when the nervous system is pushed toward higher stimulation through increased serotonin, dopamine, or adrenaline activity.
Histamine pathways may also be involved. Some individuals have genetic variants that impair histamine breakdown, which can contribute to anxiety, sleep disruption, irritability, and a sense of internal restlessness. When medications interact with these pathways, the resulting symptoms may feel unexpected and discouraging.
Recognising that these reactions are rooted in biology, rather than personal inadequacy, can be profoundly relieving.
What Precision Psychiatry Looks Like
Precision psychiatry seeks to move beyond broad categories and instead examine how a specific individual’s genes influence neurotransmitter production, breakdown, detoxification, and nutrient utilisation.
Genetic testing, often conducted through a simple cheek swab, can identify variants affecting these pathways. When practitioners understand how a patient synthesises and clears neurotransmitters, they can make more informed decisions about whether medication is appropriate, which type may be better tolerated, and whether nutritional or dietary strategies should be prioritised.
This approach does not reject conventional medicine. Rather, it enhances it by matching interventions to biological individuality.
Looking Beyond Medication Alone
While genetics provides important insights, they are only part of the picture. Brain chemistry is influenced by systemic factors throughout the body.
Inflammation can alter neurotransmitter production and receptor sensitivity. Gut health plays a significant role in immune regulation and neurochemical signalling. Nutrient status affects the enzymatic steps required to synthesise serotonin and dopamine. In some individuals, food sensitivities or histamine intolerance can trigger pronounced emotional symptoms.
Addressing these underlying contributors may improve mood stability in ways that medication alone cannot fully achieve.
When Medications Have Not Helped
For individuals who have cycled through multiple antidepressants without lasting improvement, it may be worthwhile to explore:
- Genetic testing related to neurotransmitter and detox pathways
- Comprehensive nutritional assessment
- Inflammatory markers
- Gut health evaluation
- Histamine balance
- Stress and lifestyle factors
In some cases, targeted nutritional support and dietary adjustments can enhance the body’s natural capacity to regulate mood. The aim is not to induce artificial elevation or manic states, but to restore steadiness and contentment.
A More Compassionate Understanding
Depression and anxiety are not moral failures. They are not signs of weakness or lack of effort. They often reflect complex biochemical imbalances influenced by genetics, environment, nutrition, and stress.
When individuals understand how their bodies produce, use, and clear neurotransmitters, they can shift from a cycle of guessing to a more informed, personalised approach. That shift does not eliminate every challenge, but it offers clarity and direction in place of confusion.
Precision medicine represents an evolution in how we think about mental health. Rather than asking why a person is not responding to treatment, it asks whether the treatment truly fits the person.
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Important Information: This video is for educational purposes only and is not medical advice. Always consult your healthcare provider before making dietary or supplement changes.
