We’ve Only Just Begun…

DWN Media/AdobeStock

Psychiatry truly is in its infancy. It is such a young field attempting to improve functioning and quality of life for so many diverse and complex brain disorders that it should be no surprise that our treatment outcomes spread across the spectrum from much improved to progressive decline. Through many years of psychopharmacology consultations, a common question I get is, “I’ve tried everything I can think of, but I can’t get my patient any better.” Such was the case in a recent conversation with a senior colleague whom I work with who is competent, bright, committed, and compassionate. He was describing his most challenging case, where little progress has been made over the past several years. His patient, an elderly gentleman with disabling chronic bipolar depression, has not improved over the past several years despite aggressive and appropriate complex treatment trials. My colleague concluded by stating something to the effect of, “I realize I know a lot, but I feel like there must be one more treatment option that exists that I do not know about that could get my patient better.” My observation of medical professionals is that we quickly forget the countless patients who improve with our treatments but feel frustrated and responsible for the few patients who do not improve, or whose symptoms and function steadily decline.

Additionally, some psychiatric practitioners, with good intentions, engage in excessive polypharmacy in an attempt to further improve their patients’ symptoms. This can backfire by having too many medications that cause onerous adverse events, unwanted effects, and pharmacodynamic confusion. In my experience, this happens a lot in the treatment of schizophrenia, where the well-intentioned clinician continues to add more antipsychotic medications of increasing dosages in an attempt to eliminate all psychotic symptoms. In fact, approximately one-third of patients diagnosed with schizophrenia will remain psychotic no matter what we do. We are just not smart enough yet to fully understand and more adequately treat this complex psychiatric disorder. However, any treatment-resistant patient with schizophrenia does deserve an adequate dose of clozapine, with a well-documented therapeutic 12-hour post-dose clozapine level, for an adequate duration. Trials of augmenting the clozapine with a second antipsychotic should be systematically tried. Additionally, the many non-psychopharmacological treatments should also be aggressively implemented. My point is that we should aggressively treat any patient with evidence-based comprehensive protocols, realizing that despite our efforts, some patients will not improve. We have much to learn about the brain and mental illness, and our current cutting-edge treatments will eventually be retired to the archives of psychiatry, replaced by the next generation of treatments.

My experience in science in general, and medicine in particular, is that on any given day there is an inflated, grandiose, albeit naive belief that we are at the cutting edge of knowledge, with better treatments and hypotheses than we have ever had, and it is just a matter of filling in the details to complete our mastery. History, of course, consistently dispels this mythology, leaving the next generation to speak with amusement and critical judgement of what was the cutting edge at some past time. One of my favorite quotes related to the evolution of knowledge in science, although a bit harsh, is, “Old scientists don’t adopt new hypothesis; they simply die off.”

Insulin Shock Therapy

Psychiatry has a long track record in a short period of time of developing new treatments, learning from our patients the treatments’ true value, and then discarding what is not helpful or is harmful and improving on treatments that are helpful but not optimal. Let’s take a walk down memory lane.

It was less than a century ago, in 1927, that insulin shock therapy began its tenure as a psychiatric treatment when Austrian-American psychiatrist Manfred Sakel promoted its use. It was primarily used to treat schizophrenia and involved large doses of insulin being injected repeatedly during the period of several weeks to induce comas.^1,2 Throughout the 1940s and 1950s, it was a common treatment modality for schizophrenia in the US until it fell into disfavor as pharmacotherapy became available with the entry of chlorpromazine as the first antipsychotic medication in 1954. In retrospect, insulin shock therapy is an embarrassment to our field with the advantage of 20/20 hindsight, and it is rarely spoken of.

Electroconvulsive Therapy

Electroconvulsive therapy (ECT) had its entry as a treatment in psychiatry in 1938.^3,4 Prior to using electricity to induce a seizure, in 1934, neuropsychiatrist Ladislas Meduna, considered the father of convulsive therapy,⁵ initially induced seizures with camphor and then pentylenetetrazol (metrazol, Cardiazol). Meduna hypothesized that epilepsy and schizophrenia were antagonistic disorders and, hence, inducing a seizure would reverse schizophrenia.

ECT—once established as much safer, easier to administer, and less expensive than Cardiazol—quickly replaced it and was widely used during the 1940s and 1950s. Although its use waxed and waned over the decades, it remains an important psychiatric treatment today. A major issue that fueled the controversy about treatment with ECT was ensuring that patients gave informed consent whenever possible. ECT is currently primarily used for treatment-resistant major depressive episodes, treatment-resistant catatonia, and severe and refractory mania.

Lobotomy

Arguably the darkest treatment filed deep in the historical archives of psychiatry is the lobotomy, also known as a leucotomy. Through a maze of extrapolations and theoretical hypothesis, the first lobotomy was performed in 1935 by the Portuguese neurologist António Egas Moniz. Remarkably, he shared the Nobel Prize in Physiology or Medicine in 1949 for discovering the therapeutic benefits of a lobotomy in patients with psychosis, a Nobel Prize that understandably remains controversial. During the 1940s and into the early 1950s, the number of prefrontal lobotomy procedures in psychiatric patients rapidly increased in the US, until the procedure fell into disfavor due to the negative outcomes including irreversible personality changes, often including severe apathy requiring lifelong custodial care. It has been estimated that approximately 40,000 individuals received prefrontal lobotomies in the US. One of the most famous examples was President John F. Kennedy’s sister Rosemary, who had a lobotomy in 1941, which resulted in permanent incapacitation and institutionalization. A recent biography of Rosemary painfully describes the effects on the lobotomy on her life.⁶

The Invasion of Psychopharmacology

The 1950s proved to be a revolutionary decade that laid the foundation for the use of medications to treat major mental illnesses, with mechanisms of action that had become enshrined as dogma up until the past decade. It was chlorpromazine, the first dopamine-2 receptor antagonist, that in 1954 became the foundational prototype of all US Food and Drug Administration (FDA)–approved medications to treat the positive symptoms of schizophrenia, continuing up to and including today. For the treatment of unipolar major depressive disorder, iproniazid, a monoamine oxidase inhibitor, was our first FDA-approved antidepressant in 1958, followed by imipramine, a tricyclic antidepressant, which was approved in 1959. Although mechanistically different, both medications had the overlapping effect of raising brain levels of serotonin and norepinephrine. These monoamine modulators became the prototype mechanisms for all of the subsequent FDA-approved antidepressants, until 2019, when esketamine (Spravato), an N-methyl-D-aspartate (NMDA)-glutamate antagonist, was FDA approved for treatment-resistant depression.

Diazepam (Valium), approved by the FDA in 1963 as the first benzodiazepine, revolutionized the treatment of anxiety and insomnia. It has numerous congeners with different pharmacokinetic properties to provide a range of options depending on the diagnosis and patient-specific factors. Benzodiazepines target the same receptor as alcohol, barbiturates, zolpidem (Ambien), and other drugs.

Long-Overdue Novel Agents

The past decade has ushered in novel classes of medications that are slowly gaining momentum as agents with different mechanisms of actions from the aforementioned classics, with the hope that they may provide better tolerability and improved efficacy, especially for patients who have only partially benefited, if at all, from the 60-year-old mechanistic variants. For the treatment of unipolar major depressive episodes, there are now 2 FDA-approved NMDA-glutamate receptor antagonists: esketamine (Spravato) and dextromethorphan/bupropion (Auvelity), with well-established clinical use. KarXT, currently under review by the FDA for the treatment of schizophrenia, has no affinity to dopamine or other monoamine systems. Rather, it is an agonist at the muscarinic cholinergic 1 and 4 receptors in the brain, which is believed to decrease presynaptic dopamine release rather than increasing postsynaptic dopamine-2 receptor antagonism. The medication pipeline for other novel agents is robust and includes a wide range of novel mechanisms of action.^7,8

Interventional Psychiatry

ECT, one of our earliest treatments that remains in our treatment portfolio, paved the way for several nonmedication interventional treatments that hold promise for the future. On the top of the list is repetitive transcranial magnetic stimulation, which continues to improve in regard to both technology and clinical applications. Vagus nerve stimulation has proven effective for some patients with treatment-resistant depression. Deep brain stimulation (DBS) was FDA approved for Parkinson disease and essential tremor in 1997, dystonia in 2003, obsessive-compulsive disorder in 2009, and epilepsy in 2018. DBS is currently being studied in clinical trials at some medical centers for treatment-resistant depression and other treatment-resistant disorders.

Concluding Thoughts

I can imagine a time 100 years from now when an editorial is written by a psychiatrist reflecting on the history of psychiatric treatments over the previous 200 years. I fully expect this psychiatrist to chuckle or frown with dismay as our present-day treatments are written about and criticized. That is the evolution of science, medicine, and psychiatry. It is likely that we will be utilizing treatments well beyond our current imagination. Artificial intelligence, computer science, and electrical engineering will likely be involved in at least some of these treatments. Medications as we know them will likely have disappeared from our armamentarium. Our understanding of the beautiful brain will have advanced exponentially.

If I had a crystal ball, in addition to these advances, I hope that I would see 3 established norms, as follows, that could actually exist today, if we could only find a way to work together to do no harm and provide the best for our patients:

Stigma of all types, especially in mental health, would have disappeared.

Every individual would have equal and timely access to every treatment available, based on clinical need and not insurance companies, administrators, political agendas, and tiered benefit plans.

Academic medical centers, hospital and clinic systems, health professional training programs, and frontline clinicians would be excited and proud about partnering with the pharmaceutical industry to collaborate on treatments in the pipeline, communicate about newly approved treatments, and provide immediate access to novel treatments as they become FDA approved.

Dr Miller is medical director, Brain Health, Exeter, New Hampshire; editor in chief, Psychiatric Times; staff psychiatrist, Seacoast Mental Health Center, Exeter; and consulting psychiatrist, Insight Meditation Society, Barre, Massachusetts.

References

1. Modern psychiatry in practice. Ment Health (Lond). 1948;7(4):105.

2. Jones K. Insulin coma therapy in schizophrenia. J R Soc Med. 2000;93(3):147-149.

3. Berrios GE. The scientific origins of electroconvulsive therapy: a conceptual history. Hist Psychiatry. 1997;8(29):105-119.

4. Bolwig TG. How does electroconvulsive therapy work? Theories on its mechanism. Can J Psychiatry. 2011;56(1):13-18.

5. Fink M. Meduna and the origins of convulsive therapy. Am J Psychiatry. 1984;141(9):1034-1041.

6. Larson KC. Rosemary: The Hidden Kennedy Daughter. Mariner Books; 2015.

7. Miller JJ. Medication pipeline: schizophrenia and PTSD. Psychiatric Times. 2024;41(1):1,9-12.

8. Miller JJ. Medication pipeline: antidepressants and ADHD Rx. Psychiatric Times. 2024;41(2):1,5-7.