John J. Miller, MD

The phrase “no free lunch” has its root in the mid-1800s United States. Beginning in that time period, bars and saloons offered free food at their establishments as long as you bought a drink. The merchants knew that their generous investment in free food for their customers would pay for itself many times over with the profits made from the beverages. Simply put, nothing is for nothing.

In the practice of medicine, we are all too familiar with this simple concept: No matter what benefit our treatment plan provides for our patients, there is always a cost. Our ethical responsibility is to provide 

 to our patients about the potential benefits, side effects, adverse effects, and rare serious risks from any agreed-upon treatment plan. Ideally, our menu of possible treatments should be comprehensive and should include many elements that go beyond the scope of our expertise, including the option of no treatment.

Let’s look at a common psychiatric disorder—a major depressive episode—and review the treatment complexities that are involved. Our first task is to complete a comprehensive psychiatric evaluation, collecting a treasure trove of information that often directs our recommended treatment options. We must consider the many possible 

 that, on the surface, look like a straightforward major depressive episode, such as: various medical conditions, newly started medication or over-the-counter remedy, 

, drug withdrawal, bereavement, an adjustment disorder, or depression secondary to another primary psychiatric disorder (such as obsessive-compulsive disorder or an anxiety or sleep disorder).

Table. A Partial List of Treatment Modalities for Depression

Once we have established that our patient indeed is having a primary major depressive episode, the next task is to differentiate if it is secondary to unipolar depression or bipolar depression, as the treatment recommendations will be very different for each.

Let us review a partial list of the possible treatment 

 Evidence exists to support each of the listed interventions, and our patient may have a strong preference that may not include treatment with us. For many patients, a combination of several of these treatment modalities can be initiated concurrently. Over time, especially if the depression is treatment resistant, additional treatments may be explored until 1 or more of the following occurs for our patient: They reach the ideal goal of full remission from their depressive symptoms; improve from the simple passage of time; have a major change in life circumstances that helps propel them out of their depression; fire us (and hopefully see another clinician); or accept the persisting residual symptoms; or dies.

So, what about no free lunch? Each of the listed treatment interventions, including the patient’s option of no treatment, is accompanied by a plethora of potential benefits 

 (also known as adverse events), and, in some cases, the possibility of serious and even life-threatening risks. With no crystal ball, our responsibility is to inform our patient of all these possibilities and ensure that they are competent and understand this discussion. Then, we agree upon a plan with appropriate monitoring. Over my 30 years of clinical practice, my patients have taught me about many unusual side effects that I never could have predicted. Additionally, it is not uncommon that I am surprised by the treatment choice that a patient makes. My clinical philosophy has evolved to include the recognition that the more tools we have in our treatment toolbox, the greater the likelihood that we will ultimately find a treatment (or combination of treatments) to improve a given patient’s functioning and quality of life.

In this issue, we present 2 important series of articles related to psychiatry’s toolbox: a debate over the use and effectiveness of electroconvulsive therapy (ECT), and an exploration of psychiatric medications’ possible side effects. In the spirit of these articles, I would like to share a few of my memorable patient responses to treatment.

I was in private practice 25 years ago when I was asked to evaluate a man, aged 72 years, who was brought to me by his family for an emergency evaluation. He had a history of recurrent severe major depressive episodes, often complicated by mood-congruent psychotic delusions. Because this man presented virtually mute to my office, his family provided his history and current symptoms.

According to the family, he had suffered 5 previous severe depressive episodes over the prior 20 years and had not responded to aggressive trials of pharmacotherapy. There were no identifiable psychosocial stressors; when he was not depressed, he lived independently and was high functioning. His 

 began unpredictably and rapidly progressed to severe depression accompanied by hopelessness, worthlessness, helplessness, amotivation, and poor functioning. He ultimately would stop eating, make no eye contact, and sit at home “like a log.” In addition, he developed delusions that he was full of sewage and rotting from the inside out. He believed he would die, but he was not suicidal.

, as he had stopped eating and drinking and was virtually mute with delusions compromising his competence. I arranged for admission to our local community hospital’s inpatient psychiatric unit, and my colleague, who had treated the patient for similar presentations with ECT in the past, began ECT the following morning.

There was a dramatic change after the patient’s first ECT treatment: He wanted a meal, and his delusions virtually vanished. After 3 ECT treatments in the hospital, he significantly improved and continued his course of ECT as an outpatient.

I eventually learned that this was his usual presentation. He never responded to a litany of medications, but he did respond rapidly to ECT treatments. His long-term treatment consisted of 1 

 a month. However, he tested the fates every once in a while and chose to stop his ECT treatments, which was always followed by a severe delusional depressive relapse.

Several years after completing my residency training, I was working in a private group practice when I completed a seemingly straightforward psychiatric evaluation on a woman in her late 40s. She presented with a moderate episode of depression, with significant 

. I discussed treatment options with her; she was already in psychotherapy with a therapist in our practice. We agreed on a trial of 

, hoping to take advantage of its sedating properties to help her sleep, as well as decrease her anxiety.

Three days later she came in to see me for an emergency appointment. I quickly found myself being criticized and cursed by this woman. She reported that since starting the nefazodone, both her anxiety and insomnia had worsened. She fired me and transferred to another psychiatrist in our practice who put her on a different antidepressant. She responded nicely with full resolution of her depression and associated symptoms.

I was befuddled. At the time, my understanding and experience with nefazodone was that it was a reasonable antidepressant that 

 Nefazodone also had the advantages of relative weight neutrality and minimal sexual dysfunction. As psychiatry’s collective experience with nefazodone grew, however, we learned that a tiny minority of patients hypermetabolize nefazodone to a molecule called 

 (mCPP), usually a minor metabolite. In this small subgroup of patients, mCPP causes anxiety, panic attacks, central nervous system stimulation, and dysphoria. I learned important psychopharmacology from my experience with that patient; with subsequent patients, I always discussed the rare but possible risk of unpleasant side effects from nefazodone.

During my second year of residency in psychiatry at the University of Massachusetts Medical Center, I worked on the locked inpatient unit. I admitted a man in his early 60s who reported a lifelong history of recurrent unipolar major depressive episodes. When depressed, he could not function in his job, withdrew from his social relationships, became 

, was paralyzed by anxiety, and felt full of guilt and negative self-judgment. He reported that historically heresponded best to imipramine, which he usually continued for about 6 months after the depressive episodes resolved, and then discontinued it. At the time of this admission, he had been off all psychiatric medications for more than 2 years. So, I started him on imipramine.

On the morning of his third hospital day, as I walked onto the locked unit, this patient ran toward me with exuberance, praising me for turning him “from a lamb into a lion.” The staff told me he had been up all night calling old friends and business customers. Having never been hypomanic or manic in the past, he was excited and delighted over his perceived newfound exceptional functioning.

However, as is common in mildly manic patients, he remained fully competent to decide his fate. Despite a lengthy team meeting with him, in which we explained in great detail that the imipramine had flipped him into a manic state and shared the risks and unpredictability that accompanied mania, he insisted on discharge. We had to allow him to leave against medical advice.

I can still see him walking toward me that morning with such excitement and appreciation, all the while feeling dread about having prescribed the medication that transformed this man from having a major depressive episode with poor functioning into an individual with hypomania who had no insight into the 

 and regretful adventures that would likely come his way.

All experienced clinicians have had similar encounters to these. The blessing of the field of medicine is that we have numerous treatment options to draw upon, established by a solid evidence base and the accumulation of our aggregate clinical experience. The curse is that each patient is unique in ways that we cannot predict, and we have no control over how a particular patient will respond to treatments. Just as our patients have no free lunch when beginning our prescribed treatment, we have no free lunch when recommending what that treatment should be.

is medical director, Brain Health, Exeter, New Hampshire; Editor in Chief, 

; staff psychiatrist, Seacoast Mental Health Center, Exeter; Consulting Psychiatrist, Exeter Hospital, Exeter; Consulting Psychiatrist, Insight Meditation Society, Barre, Massachusetts.

Antidepressants, part 1: 100 years and counting

Nefazodone. a review of its pharmacology and clinical efficacy in the management of major depression

Articles

The more tools we have in our treatment toolbox, the greater the likelihood that we will ultimately find a treatment (or combination of treatments) to improve a given patient’s functioning and quality of life.

No Free Lunch

John J. Miller, MD, talks about the increased risk of tardive dyskinesia on a synaptic level.

is medical director, Brain Health, Exeter, NH; editor in chief,

; staff psychiatrist, Seacoast Mental Health Center, Exeter, NH; consulting psychiatrist, Exeter Hospital, Exeter, NH; consulting psychiatrist, Insight Meditation Society, Barre, MA.

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Handling aggression in patients with dementia can be difficult...

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 is medical director, Brain Health, Exeter, NH; Editor in Chief, 

; staff psychiatrist, Seacoast Mental Health Center; consulting psychiatrist, Exeter Hospital; consulting psychiatrist, Insight Meditation Society, Barre, MA.

Individuals with mental illness continue to struggle with access to treatment in the United States, including in metropolitan 

. Despite the huge unmet need for additional psychiatrists in the United States, the number of graduating medical students choosing psychiatry as their specialty training sadly remains quite low. Thomas et al 

 that approximately 96% of the 3140 US counties had an unmet need for practicing psychiatrists, and this need was higher in rural areas and areas with low per capita income.

 suggesting this shortage will only increase as current practitioners retire in the years ahead. I live in Exeter, New Hampshire, a mere hour north of Boston, Massachusetts, where the waiting time for an initial outpatient psychiatric evaluation is anywhere from 2 to 6 months.

I was introduced to my first psychiatric mental health advanced practice registered nurse (PMH-APRN) when I joined a private psychiatric group practice in 1995 in Newburyport, Massachusetts. This was a multispecialty outpatient practice with a wide range of clinical specialties: therapists of various degrees, a neuropsychologist, 6 psychiatrists, and a psychiatric nurse practitioner (psych NP—the title used at that time). To be honest, I was clueless that this advanced nursing degree even existed. Having completed my psychiatry residency training 4 years earlier, and then working in the Worcester County area since that time, I had never crossed paths with a psych NP.

Initially I was skeptical and, frankly, put off by the fact this person was prescribing medications with relatively little formal training. With the overconfidence (or maybe insecurity) of my 12 years of training in biochemistry, medical school, internship, and psychiatry residency, it was hard for me to believe that the Commonwealth of Massachusetts would license a nurse with a few years of additional training to practice clinical psychiatry—and to prescribe medications no less! The 6 psychiatrists who had worked with this psych NP for years continually reassured me that the nurse was clinically solid and competent. Over time I came to the same conclusion. We became, and remain, colleagues. I now refer patients to her without any reservation.

Over the next 10 years I served as the supervising psychiatrist to 5 PMH-APRNs in various clinical settings in Newburyport, as a legal supervision contract was required by the Massachusetts Board of Registration in Nursing. For the first 5 years, I met with these PMH-APRNs weekly. After relocating to New Hampshire and shifting my practice to a community mental health center (CMHC) in 2007, my supervision transformed to a consultation role per the New Hampshire Board of Nursing requirements. I continue to thoroughly enjoy these consultation meetings, and I remain impressed with these individuals’ clinical skills, eagerness to learn, and commitment to improve their patients’ functioning.

In New Hampshire, PMH-APRNs fill a huge void by providing psychiatric treatment that otherwise would not exist. I know this from direct personal experience. There are 10 CMHCs in New Hampshire, and collectively they employ roughly equal numbers of PMH-APRNs and psychiatrists. At our CMHC, we have 9 psychiatrists and 4 PMH-APRNs. We have increased our access in the community by having these PMH-APRNs work in our community hospital’s emergency department, spend time at the local homeless shelter, and schedule onsite hours at nearby community health centers (CHCs). Additionally, the waiting time for an initial evaluation has decreased.

Similarly, throughout the United States, CHCs and CMHCs experience a disproportional shortage of psychiatric prescribers. Over the past 20 years, one growing resource has been the utilization of PMH-APRNs. In 2010, the American Psychiatric Nurses Association chose this new title and acronym to replace 2 older titles: psychiatric nurse practitioner and psychiatric clinical nurse specialist. For the interested reader, Mary D. Moller, DNP, ARNP, PMHCNS-BC, CPRP, FAAN, provides a historical review of the specialty of PMH-APRN from its beginnings at Rutgers University in 1954 to its current status.

Currently, each state maintains its own licensing requirements and range of prescription privileges for PMH-APRNs. Yang et al 

 the number of mental health-related visits at CHCs during the years 2006 through 2011 in states where nurse practitioners had “independent practice authority” (NP-IPA), as compared with states where they did not.

 Not surprisingly, in states with NP-IPA, there was a significant increase in mental health-related treatment/prescriptions by the NPs, which demonstrates increased utilization of NPs for mental health visits in CHCs. Most recently, in the January 2021 issue of 

 from the Department of Psychiatry at Columbia University Medical Center in New York discuss how PMH-APRNs serve an important role in providing access to psychiatric treatment, especially in rural areas, urban neighborhoods, CHCs, and other settings with significant unmet mental health access. The authors describe their development of a federally qualified health center’s Community Psychiatry Nurse Practitioner Fellowship, and the success of this program.

I have lectured in 47 states, including many rural and economically deprived areas. In all clinical settings, but especially these, the majority of frontline psychiatric treatment is delivered by PMH-APRNs. The local primary care physicians, clinics, and hospitals count on them. In my view, PMH-APRNs have become well-needed colleagues that are an integral part of our national health care system and allow us to fulfill our primary oath as physicians: “Do no harm.” There simply are not enough of us psychiatrists in the United States. Period. Engaging with PMH-APRNs as essential 

 only serves to improve access and quality of treatment for all of our patients.

Let me be clear, PMH-APRNs do not have the depth of training or the clinical acumen equal to ours as trained and board-certified psychiatrists. In my experience, this should not negate the clinical knowledge and experience that they do offer, and the value they can bring to raising the level of psychiatric care to individuals experiencing mental illness.

Psychiatry is not the only field turning to this group to extend care. Most medical practices, hospitals, clinics, emergency rooms, walk-in acute care centers, CHCs, CMHCs, and other types of health care delivery utilize specialized APRNs as an integral part of their treatment teams. Two years ago, my mother’s health was rapidly declining from advanced congestive heart failure, which resulted from open heart surgery at age 39 at the Massachusetts General Hospital (MGH) in Boston. She remained a patient at MGH for 44 years after her open heart surgery. During the last year of her life, I would bring her intermittently to meet with her 

 team at MGH, which included 3 different cardiology subspecialists. Significantly, for every 2 of her 3 monthly visits she was evaluated exclusively by a cardiac APRN. After my mom died, we sent flowers to this cardiac APRN in appreciation of her time, skill, and compassion for my mother.

Similarly, this past fall, for my routine 10-year screening colonoscopy, my anesthesia was managed by a nurse anesthetist. I had full confidence in her competence. Due to a health 

 policy change, I recently transferred my primary care to a local family practice physician. The practice consists of himself, a family APRN, and a physician’s assistant. My first appointment was with the APRN, and I left feeling good about my new health care team.

PMH-APRNs have become an integral part of health care in the United States. For us in psychiatry, I consider them an integral part of our treatment teams: psychiatrists, PMH-APRNs, psychiatric nurses, psychologists, neuropsychologists, pharmacists, therapists, case managers, occupational therapists, emergency service clinicians, students in training of all types, and more. What is important is that each professional member on Team Psychiatry knows what we each know, what we don’t know, and to seek out consultation as needed. Each of us has unique training, responsibilities, limitations, and value. Collectively we can rise to the challenge of providing quality mental health care in all treatment settings in the United States.

1. Thomas KC, Ellis AR, Konrad TR, Holzer CE, Morrissey JP. 

County-level estimates of mental health professional shortage in the United States

2. Butryn T, Bryant L, Marchionni C, Sholevar F. The shortage of psychiatrists and other mental health providers: Causes, current state, and potential solutions. 

Advancing the role of advanced practice psychiatric nurses in today’s psychiatric workforce

4. Yang BK, Trinkoff AM, Zito JM, et al. 

Nurse practitioner independent practice authority and mental health service delivery in US community health centers

A community psychiatry nurse practitioner fellowship: preparing nurse practitioners for mental health workforce expansion

This article was originally posted ahead of print on February 10, 2021, and has since been updated. -Ed

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Providing quality mental health care in all treatment settings requires one crucial element: teamwork.  

Psychiatry 2021: Team Psychiatry 

John J. Miller, MD, talks about approved treatments for early, mild-to-moderate dementia, one of which makes an appearance in "The Odyssey." 

What dementia treatment makes an interesting appearance in classical literature? 

The Odyssey

, I would like to thank each and every one of our contributors for making the Black History Month series impactful, current, and relevant to advancing the conversation about equality in psychiatry and the world. 

Special thanks to Frank Clark, MD, Diversity & Inclusion section editor, for marshalling the project. Please enjoy each of this month’s pieces.

Mentorship: Salute to a Windy City Educator

Balkozar Adam, MD, Rameshwari V. Tumuluru, MD, and Sarah H. Arshad, MD

Why Psychiatry Training Must Include Discussions on Structural Racism

Black Americans’ Distrust of the COVID-19 Vaccine

Why Is Black History Month Important to Psychiatry?

Race and Opioids: Lessons From the Civil War-Era Opioid Addiction Crisis

H. Steven Moffic, MD, and Rahn Bailey, MD: 

If I Had a Hammer: Advancing the Conversation in Psychiatry and Racism

Purcell Pearson: A Young Black Man Who Dreamt of Becoming a Psychiatrist

7 Black Physicians That Made History in the Mental Health Field

, History of Psychiatry section editor for 

 is medical director, Brain Health, Exeter, NH; editor in chief,

As February comes to a close, we reflect on this month's contributions.

A Tribute to Black History Month

John J. Miller, MD, goes over the specifics of dementia and its varied presentations. 

Cognitive disorders are varied and complicated, and require a close eye...

Looking Closely at the Types of Dementia

Scott Donofrio, MD, offered the following feedback to my article “

The Psychiatric Pipeline: 10 Agents to Watch

“In the 4th paragraph of the 2nd section (SEP-856: TAAR-1 and 5HT1A Agonist), Dr Miller has written caffeine’s action at heterodimeric adenosine receptor–D2R complexes is that of “a noncompetitive antagonist at the adenosine site.” As further described, the action seems to me to be that of a competitive antagonist with respect to adenosine and a noncompetitive one with respect to dopamine. Is that what Dr Miller means here?”

Dr Donofrio is correct with regards to my mischaracterization of caffeine as a “noncompetitive antagonist at the adenosine site.” Further, Dr Donofrio correctly hypothesizes that caffeine “seems to me to be that of a competitive antagonist w/respect to adenosine.” Caffeine is structurally similar to adenosine. As such, as the caffeine levels in the brain increase, caffeine directly competes with and displaces adenosine’s occupation of the adenosine binding site, reversing adenosine’s effect on dopamine. This, by definition, is the activity of a competitive antagonist.

Unlike adenosine, which decreases dopamine activity as its levels increase, caffeine has no agonistic activity at the adenosine site. Rather, caffeine functions as an antagonist, hence reversing the agonistic effects of adenosine and ultimately increasing brain dopamine levels.

Dr Donofrio’s second question (“caffeine’s action at heterodimeric adenosine receptor–D2R complexes is that of . . . a noncompetitive one w/respect to dopamine. Is that what Dr Miller means here?”) raises an important issue about the definition of a noncompetitive antagonist. In this situation, caffeine is not interacting with the physical D2R receptor in any way, rather its effect is indirect through the adenosine receptor, which together form a heterodimer.

There are 2 accepted definitions of a noncompetitive antagonist, which are mechanistically quite different. The first is that a noncompetitive antagonist is functionally an allosteric antagonist. With this definition, caffeine would putatively bind to a part of the adenosine receptor, which is distinct from and geographically unrelated to the adenosine binding site. However, the caffeine would alter the physical structure of the adenosine receptor to such a degree that it would not function, despite the presence of adenosine.

The second definition of a noncompetitive antagonist would be a drug/molecule that binds irreversibly to the receptor binding site. In this example, caffeine would putatively bind irreversibly to the actual adenosine binding site, so the adenosine receptor is permanently disabled. There can be no competition for binding between caffeine and adenosine because adenosine would not be able to displace the irreversibly bound caffeine.

In conclusion, caffeine is a competitive antagonist at the adenosine binding site, but has no direct activity at the dopamine-2 receptor.

One final clarification regarding this article: the print issue has a typographical error in the 10th section, 

ALKS 3831: combination of olanzapine and samidorphan

. The print article reads as follows: “Olanzapine needs no introduction, as it was FDA approved as our 3rd atypical antipsychotic in 1966, following clozapine and risperidone.” It wrongly states the FDA approval of olanzapine as “1966,” when it was actually FDA approved in 1996. The online article is correct.

is Medical Director, Brain Health, Exeter, NH; Editor in Chief,

Staff Psychiatrist, Seacoast Mental Health Center, Exeter, NH; Consulting Psychiatrist, Exeter Hospital, Exeter, NH; Consulting Psychiatrist, Insight Meditation Society, Barre, MA.

1. Miller JJ. The psychiatric pipeline: 10 agents to watch. 

https://www.psychiatrictimes.com/view/psychiatric-pipeline-10-agents-watch

2. Ferré S. Caffeine: neurobiological and psychiatric implications. 

Our Editor in Chief addresses a question from our readers about caffeine. 