The Early Years of Psychiatric Medicines and When They Didn't Work: The Untold Truth

The history of psychiatric medicines is long and complicated, with both breakthrough wins and well-known failures. By looking at the past of these studies, you can see why many psychiatric drugs still have trouble showing they work, even though medical science has come a long way.

The early years and history of psychiatric medication

Historical Background of Psychiatric Medications

Psychiatric drugs have been around since the middle of the 20th century, when antipsychotics and antidepressants were first made available. These drugs changed the way mental health care was provided and helped many people deal with their illnesses better.

Antipsychotics: The first antipsychotic drug was chlorpromazine, which came out in the 1950s. It set the stage for others that helped people with schizophrenia live more typical lives by easing their symptoms.

Antidepressants: Similarly, the finding of tricyclic antidepressants and then selective serotonin reuptake inhibitors (SSRIs) was a big step forward in the fight against depression.

Despite these improvements, many early studies showed that drugs were not always as effective as they could be.

High rates of failure in clinical trials

Researchers have found that psychiatric drugs come with some of the highest rates of failure in clinical studies when compared to other types of drugs.

Success Rates: About 6.2% of psychiatric drug candidates that go into clinical research are approved by the government. This is a lot less than in other fields, which shows that there is a problem with the way psychiatric drugs are developed overall [1]. This low rate of success shows just how complex psychiatric illnesses are and how hard it is to show that a drug works and is safe.

To simplify, several steps are involved in the process of going from medication development to market approval, and one of these is the clinical trial.
Phase I: Safety and dosage are mainly looked at, usually with fit volunteers aka people who are absolutely healthy.
Phase II: Tests the drug's effectiveness and safety in a select number of patients.
Phase III: Uses larger groups of people to prove that it works and keep an eye on any bad reactions.

The failure rates are especially high in Phase II, where only about 24% of candidates make it to Phase III. This shows that many drugs don't show enough promise in the first stages of testing 56.

Placebo Response: A big problem in psychiatric studies is that a lot of people respond to placebos. Placebos are something that doesn't work but seems and looks like a drug or treatment being tried in a clinical trial but doesn't help with what is being treated. Studies have shown that placebo effects can make up 60–80% of the effects seen with real drugs. For example, a thorough review found that the rate of placebo responses in antidepressant studies has always been between 35% and 40% [1, 6].

Things that lead to failures in effectiveness

There are a number of reasons why mental drugs don't always work or have high failure rates:

Measurements that are subjective: Clinician-reported outcomes (ClinROs) are often used in traditional outcome studies. It has been said that instruments like the Hamilton Depression Rating Scale (HAM-D) aren't accurate or trustworthy across different tests[1].
Treatment Resistance: A lot of people have drug resistance, which means that their conditions don't get better with available drugs. This effect has been seen in a number of illnesses, but it is still not being fully considered in drug development[3].
Limited Testing Methods: Because drug testing is based on already established models, there are a lot of "me too" drugs that basically minics the drugs that are already in the market. Most of the time, they only have small changes to their affects or structure.
Most of the time, these drugs don't give you new ways to treat a disease. Instead, they just copy the effects of current drugs without making any big changes.. This makes it harder to come up with new ideas and make treatments work better.[2] [5].

Important Studies and Figures

How Well Clozapine Works: Clozapine is still one of the few medicines that has been shown to help people with schizophrenia that doesn't respond to other treatments. It worked better than other antipsychotics, but it has bad side effects that make it hard to use [2, 3].
Meta-analysis: A meta-analysis found that antidepressants proved to have a mild impact on easing depression, anxiety, addiction and other symptoms when used for a long time, while antipsychotics which are used to treat severe mental health conditions like schizophrenia and bipolar disorder had better result when used for a long time, which suggests that they help a lot in keeping schizophrenia symptoms from coming back. These numbers show how different drug groups have different levels of effectiveness[4].

The Future of Making Psychiatric Drugs: What's next?

As researchers keep looking for new ways to treat mental illness, a few promising options keep coming up:

Digital Measures: Using digital health technologies (DHTs) in clinical trials has the potential to give more accurate data about how patients respond, and this could lead to better study outcomes[1].
Personalized Medicine: More and more people are realizing that treating mental health disorders with a "one size fits all" method is not enough. In the future, researchers may focus on making medicines that are tailored to each patient's unique needs [3, 6]

The long history of studies on psychiatric drugs shows a complicated picture with both big steps forward and big problems to solve. Early breakthroughs changed mental health care, but problems with effectiveness and failed trials show that more study and new ideas are needed in the field. By facing these problems head-on, we can hopefully find better ways to treat mental health issues and help those experiencing them.

References:

Reiter, J. E., Nickels, S., Nelson, B. W., Rainaldi, E., Peng, L., Doraiswamy, P. M., Kapur, R., Abernethy, A., & Trister, A. (2024). Increasing psychopharmacology clinical trial success rates with digital measures and biomarkers: Future methods perspective. Nature Reviews Psychiatry, 7. https://doi.org/10.1038/s44277-024-00008-7
Naylor, C. D., & Gafni, A. (2013). The role of placebo in clinical trials: A review of the literature. BMC Medical Research Methodology, 13(1), 1-9. https://doi.org/10.1186/1471-2288-13-66
Fava, M., & Davidson, K. G. (2000). Definition and epidemiology of treatment-resistant depression. Psychiatric Clinics of North America, 23(4), 881-895. https://doi.org/10.1016/S0193-953X(05)70050-2
Ghaemi, S. N., & Rosenquist, K. J. (2015). Efficacy of psychiatric drugs: A review of the evidence. Psychiatric Times. Retrieved from https://www.psychiatrictimes.com/view/efficacy-psychiatric-drugs
McGorry, P. D., & Yung, A. R. (2003). A brief history of psychiatric drug development: Lessons learned and future directions. The British Journal of Psychiatry, 182(43), s3-s8. https://doi.org/10.1192/bjp.182.s43.s3
Leucht, S., et al. (2023). The effectiveness of antipsychotic medications: A systematic review and network meta-analysis of randomized controlled trials in schizophrenia and related disorders. Nature Reviews Psychiatry. https://doi.org/10.1038/s41386-023-01690-5
Hyman, S. E., & Fenton, W. S. (2021). The role of biomarkers in psychiatric diagnosis and treatment: A review of the literature and future directions for research. Psychological Medicine, 51(9), 1456-1464. https://doi.org/10.1017/S0033291721000122
Tohen, M., & Vieta, E. (2018). The history and evolution of antipsychotic drugs: Lessons learned and future directions for research and treatment in schizophrenia and bipolar disorder. Nature Reviews Neuroscience, 19(1), 1-12. https://doi.org/10.1038/nrn2018