The DSM has been useful for identifying and treating mental illness, but its categories do not line up with modern neuroscience or explain causes (Morris and Cuthbert, 2012). This raises questions about the accuracy of its diagnostic categories. A new approach is needed, like RDoC, which aims to promote mental health research from a sturdier foundation: neuroscience (Morris and Cuthbert, 2012).

A Brief History of the DSM

The following timeline comes from the American Psychiatric Association with relevant interjections from the timeline of the chemical imbalance hypothesis.

• 1840:   The USA census looked for a method of collecting statistical information regarding the frequency of idiocy/insanity in the USA population

• 1880:   Seven categories of mental health were determined, still for the purpose of the census: mania, melancholia, monomania, paresis, dementia, dipsomania, and epilepsy

• 1917:   The American Medico-Psychological Association and National Commission on Mental Hygiene developed a system to collect health information from mental hospitals. Integration with the healthcare system, gave more importance to clinical usefulness than past methods of classification.

• 1921:   The APA and New York Academy of Medicine developed a classification system meant primarily for diagnosing patients with severe conditions.

• 1943-47:   The US Army Neuropsychiatry Division, then later the Veterans Administration released a modified system which suited war veterans better. They introduced a framework shift towards the idea that mental illnesses can be caused by experience.

• 1952:   The APA published a variant of the International Classification of Diseases (ICD) as the first edition of the DSM, heavily influenced by the Veterans Administration classification. This version featured the term “reaction” following the need for classification of the disorders developed post-war .

• 1965:   Chemical imbalance is proposed as the cause of depression, due to the early evidence that reserpine caused depressive symptoms, while MAOIs (early anti-depressants) lifted patients’ moods (Schildkraut, 1965)

• 1966:   Jacques van Rossum postulated that schizophrenia is the result of overstimulation of dopamine receptors, since drugs which blocked dopamine reduced hallucinations, the cause of the hallucinations must be too much dopamine (Seeman 2021)

• 1968:   The APA released the updated DSM-II, which was very similar to the original DSM, but removed the term “reaction”, shifting back towards a medical model inline with the ICD-8.

• 1973:   Homosexuality was removed from the DSM-II

• 1980:   APA published the DSM-III, which included important changes from past classification methods. Diagnostic criteria was made clear. The DSM-III took a neutral stance with regards to causality. Research during this time aimed to construct and validate these diagnostic criteria.

• ‘80-90s:   “Chemical imbalance” became a household name when Prozac was launched and pharmaceutical marketing oversimplified the hypotheses, portraying depression as a chemical deficiency that can easily be fixed by their medication.

• 1994:   APA published the DSM-IV. There was an important shift from -III in that the DSM-IV was based on empirical data, rather than by committee decision.

• 2013:   After 13 years of work, the APA published the DSM-5. Changes from -IV were based on research aimed at recognized gaps in the current research body.

• 2022:   The DSM-5-TR was published with modifications meant to remove out-of-date material, though no conceptual changes were made to the diagnostic criteria sets.

The DSM was developed as a necessity for recognizing people who need psychological treatment. With influence from the chemical imbalance hypothesis, research sought to confirm and refine the classifications of the DSM, originally determined by committee.

The DSM is a good tool for doctors to efficiently recognize conditions seen before, but has no historical basis in etiology.

The Chemical Imbalance Hypothesis

Placed in the history of the DSM are major milestones in the story of mental illnesses as a chemical imbalance. Initially suggested as a hypothesis based on seeing reduced depressive symptoms when patients were given monoamine oxidase inhibitors or MAOIs, early anti-depressants (Schildkraut 1965). Correlations between schizophrenia and dopamine were made a year later in 1966 by researcher Jacques van Rossum who suggested that hallucinations were the result of too much dopamine.

To this day, it remains a theory that mental illnesses are a result of chemical imbalances in the brain, while researchers continue to try to find biomarkers for the diagnostic categories in the DSM and investigate alternative explanations. Nevertheless, it is a commonly held opinion that chemical imbalances cause mental illnesses, especially depression. That is thanks to the pharmaceutical industry.

A Brief History of Prozac / Zoloft

The following timeline comes from Psychology Today (Ruffalo):

• 1970:   Eli Lilly, a pharmaceutical company, began their research into an alternative anti-depressant drug to tricyclic antidepressants which were known to have side effects like weight gain and cardiovascular risks.

• 1972:   The Lilly team discovered a variation on a diphenhydramine (type of antihistamine found in Benadryl) which inhibited serotonin reuptake, thus increasing the levels of serotonin in the brain, or “SSRI”. They called it “Lilly 110140”

• 1975:   “Lilly 110140” was renamed “fluozetine”

• 1987:   Fluoxetine (branded as Prozac) received FDA approval for the treatment of major depression

• 1990:   Prozac is widely used, the best-selling antidepressant ever.

• 1990s:   “Mildy depressed” becomes a new diagnosis and doctors are comfortable to prescribe Prozac, since the side effects are minimal.

• 1992:   Pfizer introduced another SSRI, called Zoloft, and referenced the chemical imbalance hypothesis in their aggressive advertising campaign.

Following the discovery and promotion of SSRI medications, more people were identified as being “mildly” depressed and the notion was made popular that this was a result of a chemical imbalance.

Research Domain Criteria (RDoC)

The diagnoses listed in the DSM-5 do not match the organization of neural circuits revealed by the tools of modern neuroscience (Morris and Cuthbert, 2012). While the DSM-5 has been very successful in helping doctors categorize and treat mentally ill patients, this method of understanding diagnostic categories has failed as a basis for discovering causality (Morris and Cuthbert, 2012).

The DSM works well for doctors, but its categories prove to be a poor starting point to understand the cause.

Since the DSM has been so successfully applied in healthcare, it has been widely adopted into surrounding regulatory systems, like insurance reimbursement, clinical trials, grant applications, and journal publications (Morris and Cuthbert, 2012).

The pervasiveness of the DSM has become an obstacle to real change in terms of how we approach mental health research.

The RDoC is a research framework developed by the National Institute of Mental Health (NIMH). It suggests that mental illnesses should be understood starting from biology and behaviour, rather than existing diagnostic categories (Morris and Cuthbert 2012). 

This is counter to traditional DSM-based research, where a group of people with DSM classified depression may be compared against a control group, in order to search for a biomarker for the specific disorder. In RDoC-oriented research, the category of “depression” is not a starting point. Rather, a certain neural circuit or system is studied to understand its function or malfunction (Morris and Cuthbert 2012). 

RDoC transcends diagnostic categories, opening the minds of researchers to “out of the box” theories towards the etiology of mental illnesses.

RDoC Progress

In 2022, ten years after publishing the RDoC initiative and matrix of research topics, Dr. Bruce Cuthbert, a co-author on the paper proposing the framework, reviewed the progress and interest in the initiative so far.

There are nearly 500 grants available, at the time of the report, for research topics referencing RDoC, funded by more than NIMH (Cuthbert, 2022). After ten years, a Google search for “RDoC” returned 150,000 hits including scientific reports, commentaries, clinical considerations and more (Cuthbert, 2022).

Diagnostic boundaries are not considered as strictly as previously and the term “transdiagnostic” has shown up more in literature since RDoC began (Cuthbert, 2022). New and promising treatments based on the biological systems related to various disorders are being invented and tested (Cuthbert, 2022). For example, a kappa-opioid blocker as treatment for anhedonia (Krystal et al. 2020).

This shift toward a biological framework marks a promising advance beyond the limitations of the DSM-5.

References

American Psychiatric Association. “DSM History.” Accessed 2026.

Cuthbert, Bruce N. “Research Domain Criteria (RDoC): Progress and Potential.” Curr Dir Psychol Sci, vol. 31, no. 2, 2022, pp. 107-117, https://pmc.ncbi.nlm.nih.gov/articles/PMC9187047/.

Krystal, Andrew D., et al. “A randomized proof-of-mechanism trial applying the 'fast-fail' approach to evaluating κ-opioid antagonism as a treatment for anhedonia.” Nat Med, vol. 26, no. 5, 2020, pp. 760-68, https://pubmed.ncbi.nlm.nih.gov/32231295/.

Morris, Sarah E., and Bruce N. Cuthbert. “Research Domain Criteria: cognitive systems, neural circuits, and dimensions of behavior.” Dialogues Clin Neurosci, vol. 14, no. 1, 2012, pp. 29-37, https://pmc.ncbi.nlm.nih.gov/articles/PMC3341647/.

Ruffalo, Mark L. “The Story of Prozac: A Landmark Drug in Psychiatry.” Psychology Today, 12 January 2026, https://www.psychologytoday.com/ca/blog/from-freud-to-fluoxetine/202003/the-story-of-prozac-a-landmark-drug-in-psychiatry.

Schildkraut, J. J. “The catecholamine hypothesis of affective disorders: a review of supporting evidence. 1965.” Neuropsychiatry Clin Neurosci., vol. 7, no. 4, 1965, pp. 524-33, https://pubmed.ncbi.nlm.nih.gov/8555758/.

Seeman, Mary V. “History of the dopamine hypothesis of antipsychotic action.” World J Psychiatry, vol. 11, no. 7, 2021, pp. 355-364, https://pmc.ncbi.nlm.nih.gov/articles/PMC8311512/.