What Sisyphus Can Teach Us About Psychiatric Drug Development

By Hannah Barnett

A popular metaphor for futile and repetitive labour comes from Greek mythology, in which Zeus condemns King Sisyphus to eternally roll a massive boulder up a hill, only for it to tumble back down just before reaching the summit.

In a new editorial published in the Journal of Psychopharmacology, David Nutt considers whether modern psychopharmacology has fallen into its own Sisyphean cycle through the relentless pursuit of highly specific psychiatric drugs.

These drugs target one precise receptor, enzyme, or neurotransmitter system, pursued out of the belief that greater specificity would lead to safer, cleaner, and more effective treatments. Yet despite enormous scientific advances, progress in the development of fundamentally new psychiatric medicines has been slow.

For Nutt, it may be time to question whether “specificity” should remain psychiatry’s ultimate goal.

The problem with the “one target” model

Nutt highlights three significant reasons why narrowly targeted psychiatric drugs consistently fail to deliver clinical breakthroughs.

1. Most mental health conditions are not caused by one single biological abnormality. Unlike many physical illnesses, conditions such as depression, schizophrenia, and anxiety do not appear to come from one gene, chemical, or brain mechanism.

2. The brain works through many connected systems at once. The brain is not a simple machine with “on/off switches”, but instead is controlled by overlapping systems working together simultaneously. This means that changing one brain chemical may have a limited effect, because other systems continue compensating or functioning alongside it.

3. Mental health conditions involve broad brain networks, not just one target. Many psychiatric disorders appear to involve patterns of activity across large brain circuits rather than one specific receptor or pathway. This makes it difficult to develop highly precise drugs. Even if researchers successfully target one small part of the system, it may not substantially change the wider brain patterns linked to the condition.

Psychiatry’s most effective treatments were often unexpected

According to Nutt, many of psychiatry’s most effective treatments were not born from elegant neuroscience theories, but from serendipity and empirical observation.

Examples include:

• chlorpromazine and clozapine

• imipramine and MAOIs

• lithium

• benzodiazepines

• electroconvulsive therapy (ECT)

• more recently, psychedelics and ketamine

Many of these treatments are pharmacologically “messy,” meaning they affect several brain systems at once. Historically, this lack of precision has often been viewed as a weakness. However, Nutt argues it may actually help explain why many of these treatments work.

Rather than targeting one narrow symptom pathway, these compounds may influence broader patterns of brain activity and communication.

Moving beyond the “one receptor, one disorder” model

Nutt proposes several directions for the future of psychiatric drug development.

Better serendipity

Psychopharmacology has increasingly focused on designing drugs to target very specific biological mechanisms. Nutt argues there may be value in placing greater emphasis once again on observation and unexpected discoveries.

This does not mean studying random effects without direction; but rather paying closer attention to patterns emerging in real-world patient experiences, population health data, and reports from clinicians and people using drugs themselves. For example, if large numbers of people consistently report improvements in wellbeing, mood, trauma symptoms, addiction, or quality of life associated with particular substances, it warrants further scientific investigation, regardless of whether the mechanisms are fully understood.

This could include better systems for collecting patient-reported outcomes, analysing large healthcare datasets, and examining broader measures of wellbeing across populations, rather than focusing exclusively on narrow biological targets.

Multi-target drugs

Instead of developing drugs that act on only one receptor or brain chemical, future psychiatric medicines could be intentionally designed to affect several systems at once.

This may better reflect the reality that conditions such as depression, PTSD, anxiety, and psychosis are shaped by many interacting brain systems rather than one isolated biological problem.

Importantly, Nutt is not suggesting a return to poorly understood or indiscriminate drug design. Rather, he argues for treatments developed with the understanding that mental health conditions involve complex and interconnected brain processes.

Network-changing treatments

Nutt also highlights treatments that appear capable of changing broader patterns of brain activity itself.

This is where psychedelics and ketamine become especially relevant. Rather than simply dampening symptoms, these compounds may temporarily interrupt rigid patterns of thought, emotion, and behaviour while also increasing the brain’s ability to adapt and form new connections.

Many researchers believe that this potential “window of plasticity” may help explain why psychotherapy, integration, and environmental context appear so important to therapeutic outcomes.

Psychedelics and a different model of treatment

For Nutt, psychedelics represent more than simply another drug class. They are presented as part of a fundamentally different treatment paradigm.

Traditional psychiatric medications are often designed to manage symptoms through regular, ongoing use. Psychedelics, by contrast, may work differently: rather than simply suppressing symptoms, they can produce short-term changes in consciousness and patterns of brain activity that may create opportunities for psychological change, new perspectives, and relearning.

Nutt also notes growing interest in so-called non-hallucinogenic neuroplasticity-promoting compounds, though research in this area remains early and highly exploratory.

Implications for regulators and industry

The moves beyond specificity and towards broader approaches could require shifts in both pharmaceutical development and regulation.

Nutt argues that industry and regulators may need to become more comfortable with:

• drugs that act through multiple mechanisms

• treatments whose full mechanisms are not immediately understood

• combining different medications in thoughtful and evidence-based ways to improve treatment outcomes

• medicines delivered alongside psychotherapy

• clinical trials where placebo blinding may be difficult

These challenges are especially relevant for psychedelic research, where subjective effects make conventional double-blinding notoriously difficult.

A broader rethink for psychiatry

The editorial ultimately raises the broader question: has psychiatry spent too long searching for highly precision solutions to conditions that are fundamentally complex and interconnected?

For decades, psychopharmacology has operated under the assumption that more specific drugs would lead to better treatments. But if mental health conditions arise from disruptions across wider brain systems rather than one isolated biological problem, future progress may depend less on narrowly targeted drugs and more on approaches that work across multiple systems at once.

Rather than focusing only on how precisely a drug targets one receptor, the more important question may be whether it can meaningfully help shift harmful patterns of brain activity, thought, and behaviour toward recovery.