“Not yet supported by trials” is not the same as “disproved”—and it should never become a reason to stop thinking.
For more than 35 years, my work in psychiatry has been guided by a simple observation: patients with the same diagnosis frequently respond very differently to the same treatment.
One patient benefits dramatically from an antidepressant, while another experiences little improvement or intolerable adverse effects. One individual can discontinue an SSRI without difficulty, while another develops prolonged withdrawal symptoms. A nutritional intervention may transform one patient’s mood, cognition or energy and appear to do very little for another.
These differences are not inconveniences that interfere with psychiatric research. They are central to understanding mental illness.
“No evidence” does not mean “no value”
Evidence-based medicine has made enormous contributions to clinical care. Controlled trials help protect patients from ineffective or dangerous treatments. They allow us to compare interventions, identify common adverse effects and challenge the biases that naturally accompany clinical practice.
But the phrase “there is no evidence” is often used too broadly.
- The hypothesis has been carefully studied and found to be incorrect.
- The available studies are small or methodologically weak.
- The treatment has never been adequately studied.
- No organization has been willing to fund the research.
- The intervention cannot easily be patented or commercialized.
- Traditional trial designs are poorly suited to the complexity of the question.
These are very different situations. An absence of research is not proof of absence. A hypothesis that has not been investigated should not be presented as established fact—but neither should it automatically be dismissed. The scientifically honest conclusion is often: “We do not yet know.”
Clinical observation frequently comes first
Many important medical discoveries began with observation, curiosity and the willingness to recognize an unexpected pattern.
Thirty years ago, I began discussing and using low-dose lithium orotate because I repeatedly observed meaningful clinical improvements in patients. At the time, there was little research to support its use, and many colleagues dismissed it without examining either the biological rationale or the clinical outcomes.
The same pattern has occurred throughout nutritional and integrative psychiatry. There was once little meaningful psychiatric research on ultra-processed food. Vitamin D deficiency was rarely considered relevant to depression or suicide risk. The microbiome, inflammation, insulin resistance, mitochondrial function and metabolic psychiatry were largely absent from conventional psychiatric education.
The lack of research did not mean these relationships were biologically impossible. It meant that our research model had not yet caught up with clinical reality. Research often confirms what careful clinicians have observed for years.
The limitations of commercially driven research
Psychiatric research is expensive. Much of the evidence supporting conventional treatments has been generated or shaped by commercial funding, particularly when a patentable medication is involved.
This does not make pharmaceutical research invalid. Many medications are lifesaving, and industry-sponsored trials can be scientifically rigorous. But the funding structure inevitably influences which questions are asked.
There is a strong financial incentive to study a new medication. There is far less incentive to study inexpensive nutrients, dietary change, sleep restoration, correction of mineral deficiencies or individualized combinations of interventions.
If there is no commercially valuable product, there may be no large trial. If there is no large trial, clinicians are told there is “no evidence.” The absence of evidence can then be mistaken for evidence that the approach has no value.
This creates a self-reinforcing cycle: what receives funding becomes “evidence-based,” while what is not commercially attractive remains outside mainstream practice. That is not purely evidence-based medicine. It is evidence shaped by the economics of research.
Psychiatry cannot ignore biochemical individuality
Traditional clinical trials attempt to create uniform groups: patients with the same diagnosis receive the same intervention, and investigators measure the average response.
But the “average” patient does not exist.
Depression is not one biological disorder. Anxiety is not one biological disorder. Even within a single diagnostic category, symptoms may arise through very different pathways:
- Trauma and chronic psychological stress
- Genetic differences affecting neurotransmitter synthesis
- Vitamin or mineral deficiencies
- Thyroid, adrenal or reproductive hormone abnormalities
- Inflammation and immune activation
- Infection
- Gut dysbiosis and impaired nutrient absorption
- Insulin resistance and metabolic dysfunction
- Medication effects or withdrawal
- Sleep disorders
- Mitochondrial impairment
- Social isolation, grief and loss
Two patients may satisfy identical diagnostic criteria while having profoundly different biological and psychological contributors. Giving both patients the same treatment and averaging their responses may conceal precisely what we most need to understand.
The intervention may be highly effective for a biologically identifiable subgroup but appear only modestly effective when averaged across a heterogeneous population.
The brain cannot be separated from nutrition
The brain is among the most metabolically active organs in the body. It requires a continuous supply of amino acids, fatty acids, vitamins, minerals and energy substrates to synthesize neurotransmitters, maintain membranes, regulate inflammation and generate cellular energy.
It should be common sense that nutrient deficiencies can alter brain function.
That does not mean every person with a vitamin D, iron, zinc, magnesium, folate or vitamin B12 deficiency will develop a psychiatric disorder. Individual vulnerability depends on genetics, development, stress, trauma, other medical conditions and the presence of additional deficiencies.
For one person, a deficiency may produce few recognizable symptoms. For another—because of genetic or metabolic vulnerability—the same deficiency may become the final factor that triggers depression, anxiety, cognitive impairment or another psychiatric syndrome.
This is the essence of biochemical individuality: the same biological stressor does not produce the same outcome in every person.
Clinical experience is evidence—but not proof
Clinical experience should not be confused with proof. Clinicians can be influenced by placebo effects, selective memory, regression to the mean and the natural fluctuation of illness.
But clinical experience is still a form of evidence—particularly when observations are repeated across hundreds or thousands of patients, responses follow a biologically plausible pattern, symptoms recur when an intervention is withdrawn and improve again when it is restored.
These observations should generate hypotheses, better documentation and formal research. They should not be discarded simply because a randomized controlled trial has not yet been conducted.
The responsible clinician must hold two ideas simultaneously:
- A treatment may be genuinely valuable before definitive research is available.
- Our confidence should remain proportional to the quality of the evidence.
This requires humility in both directions. Clinicians should not present hypotheses as established facts. Researchers and academic institutions should not present unstudied ideas as disproven.
From evidence-based to evidence-informed psychiatry
I prefer the term evidence-informed psychiatry. Evidence-informed care integrates:
- The best available research
- Clinical experience
- Biological plausibility
- Objective laboratory and medical findings
- Patient preferences
- Careful monitoring of outcomes
- The patient’s individual history, genetics, nutrition and physiology
This approach does not reject science. It expands the scientific process. When evidence is strong, we should say so. When evidence is limited, we should acknowledge the uncertainty. When an idea is based primarily on clinical experience, we should describe it honestly as a hypothesis or emerging clinical model.
But “not yet proven” should never become a reflexive reason to stop thinking.
The history of medicine is filled with observations that preceded scientific validation. Progress depends on people willing to notice what does not fit the existing model, develop a plausible hypothesis and test it carefully.
Research is essential. Clinical experience is essential. Common sense is essential. Most importantly, the individual patient must remain at the center.
The goal of psychiatry should not be to force every patient into the average response of a study population. It should be to understand the many possible paths that brought this particular person to illness—and to identify the combination of treatments most likely to help that individual recover.
