Sara Robinson, MSN, RN, PMHNP-BC

As we approach the 2-year mark of the COVID-19 pandemic, the fourth wave that has swept through our country this past summer and fall continues to surge, moving from state to state. Medical teams in emergency rooms and ICUs continue to deal with the roller coaster of overfilled hospitals and exhausted personnel to periods of quiet to recover and process what is happening. For us in psychiatry, although there has been an upswing in anxiety, depression, posttraumatic stress disorder, and many other 

—both directly and indirectly caused by the SARS-CoV-2 virus—the psychiatric impact of this pandemic will be with us for years, and likely decades, to come.

Prior to COVID-19, psychiatry was already experiencing a shortage of psychiatric providers. Throughout the United States, this shortage had been primarily addressed by an increasing number of 

psychiatric mental health nurse practitioners

Nationally, based on 2021 numbers, there are over 325,000 nurse practitioners (NPs) licensed in the United States.

 Of these, approximately 5% are primarily certified in psychiatric-mental health. This percentage has been steadily growing in response to the significant shortage of psychiatric providers. With more states legislating greater independence for NPs, there has been a strong pushback by some physician groups. The authors would like to share our positive experience working in a collaborative model, which includes psychiatrists and PMHNPs at a 

New Hampshire (NH) has 10 identified catchment areas, each with its own private nonprofit contracted community mental health center. An informal survey in February 2021 determined that of approximately 100 psychiatric prescribers at these CMHCs, half were psychiatrists and half were PMHNPs. At our CMHC, there are 9 psychiatrists and 4 PMHNPs with shared responsibilities, providing direct patient care in a variety of settings. The additional psychiatric hours—available by adding 4 full-time PMHNPs—have allowed a more direct psychiatric presence at our local homeless shelter, primary care clinics, and the emergency room of our affiliated hospital. Significantly, the wait time for a medication evaluation for a new or existing patient has decreased.

A larger and more diverse psychiatric group has created an environment for more 

, with different practitioners providing input from their own clinical interests and expertise. As our chosen profession of medicine is appropriately called a “practice,” there is always more to learn and more experience to gain. We would like to present a case that highlights the benefit of working in a collaborative psychiatrist/PMHNP setting, which ultimately resulted in good patient care, as well as increased clinical acumen by all involved.

While working as a PMHNP in a CMHC, one of my patients informed me of an 

. She was in treatment for bipolar I disorder, with several prior psychiatric hospitalizations, but a recent, prolonged period of stability. Her maintenance regimen consisted of lamotrigine and lithium. Given the report of pregnancy, I knew it was necessary to reevaluate the appropriateness of the patient’s medication regimen to determine the need for any changes.

As I often do when faced with a challenging clinical situation, I consulted a colleague to discuss this case and the range of treatment options. Given the US Food and Drug Administration’s policy change in 2015 when they eliminated pregnancy categories for all approved drugs, it is important for all clinicians to continually revisit current pregnancy recommendations. A colleague initially recommended that I stop the 

, which did not seem like an ideal option for my patient. Given the constantly evolving and changing recommendations in psychopharmacology, including during pregnancy, I consulted the current literature to review the most up to date recommendations. Additionally, I sought out my colleague at the CMHC, John Miller, MD, to discuss the case. Miller provided recommendations as to how he would proceed and shared articles from his library of psychopharmacology during pregnancy.

Given my patient’s personal psychiatric history, which included multiple hospitalizations in the past for mania and depression, discontinuation of the 

 during her pregnancy would be risky. Since she had responded well to lithium for many years, and lithium treatment during pregnancy is considered a reasonable option, I decided to recommend this to her.

I reviewed a thorough risk-benefit analysis of current 

treatment recommendations during pregnancy

 with the patient and discussed some additional perinatal testing that should be done if she were to stay on the lithium. Subsequently the patient chose to remain on the lithium during her pregnancy, agreeing to increased monitoring, and informed consent of her decision was documented. She appreciated the shared decision-making process and signed a release of information to allow for coordination of care with her OB-GYN, which was important to ensure a consistent team approach with clear communication. Due to the relationship between lithium and fluid status, careful and frequent monitoring of maternal lithium dosing and levels was required throughout the progressing pregnancy, as well as immediately following delivery. The pregnancy and delivery proceeded without complications, and her mood symptoms remained stable.

Beyond the patient outcome, which was of utmost importance, this case enhanced my interest in effective psychopharmacology during pregnancy. Over time, I became a resource for my colleagues at the CMHC, who called upon me to consult on cases with pregnant patients.

This case highlights one example of how collaborative teamwork serves to benefit the patient, improves patient outcomes, and provides a constant opportunity to learn from and teach one another during our busy daily practices. Competent physicians and PMHNPs know what they know, know what they do not know, and know when to obtain consultation. In a large mixed practice, there is a greater opportunity to consult and collaborate.

The largest unmet need for access to psychiatric treatment is in rural, underserved, and socioeconomically deprived settings. Moving forward, the shortage of psychiatric providers—both psychiatrists and PMHNPs—is expected to increase. Increasing the numbers of both psychiatrists and PMHNPs is essential. Creating a collaborative and mutually respectful working environment amongst all treatment team members is essential to deliver quality patient care, minimize provider burnout, benefit from an extended network of colleagues, expand interest in our profession, and continue our lifelong learning.

is a psychiatric-mental health nurse practitioner in the Seacoast, New Hampshire area, and an clinical assistant professor and program director of the Post-Masters Psychiatric-Mental Health Nurse Practitioner Certificate Program, Department of Nursing, University of New Hampshire, Durham. 

is medical director, Brain Health, Exeter, New Hampshire; editor in chief,

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

1. NP Fact Sheet. American Association of Nurse Practitioners National Practitioners. Updated May 2021. Accessed December 9, 2021. 

https://www.aanp.org/about/all-about-nps/np-fact-sheet

Articles

Collaborative care provides the best possible patient outcomes. 

Adapting to Today’s Unmet Psychiatric Needs in the United States

Hildegard Peplau, the founder of advanced practice psychiatric nursing, was a nurse theorist and educator, and her development of the theory of interpersonal relations revolutionized nursing care.

 Peplau collaborated with Harry Stack Sullivan, MD, renowned for his contributions to interpersonal approaches to treatment and his publication of The Interpersonal Theory of Psychiatry.

 Peplau developed and implemented the first master’s-level role for advanced practice nurses to provide direct care to psychiatric patients.

 The advanced practice role shifted from clinical nurse specialist to advanced practice registered nurse in the early 1990s.

 Today, students who have successfully completed an accredited program are eligible to sit for the board certification exam through American Nurses Credentialing Center to obtain PMHNP certification.

Education is an ongoing process, however, and does not end with board certification. Board-certified PMHNPs are required to renew national certification every 5 years and must complete 75 continuing education units. In addition, nurse practitioners maintain certification by 

 and completing additional renewal requirements in domains that demonstrate continued competence.

 Additionally, all PMHNPs must meet specific state-level requirements for maintaining state licensure as both a registered nurse and a nurse practitioner; many states require renewal of these licenses every 2 years.

PMHNPs also have years of experience as professional nurses, which serve to hone their clinical judgment and assessment skills. The hands-on clinical experience of interacting with patients during prelicensure education, clinical practicum, and subsequent practice is a valuable asset. Therapeutic communication is a core skill, and the therapeutic relationship with patients is a central tenet throughout all levels of training, especially within psychiatric nursing.

Practice authority for nurse practitioners varies from state to state, ranging from full practice to reduced or 

 Many states require collaboration, supervision, or consultation with a physician for nurse practitioners to practice. Even in states without a collaborative requirement, many nurse practitioners choose to participate in formal and informal supervision with physician colleagues. Massachusetts recently joined the rest of the New England states by passing legislation to 

grant nurse practitioners full practice authority

is a psychiatric mental health nurse practitioner in the Seacoast, New Hampshire area; and clinical assistant professor and program director of the Post-Masters Psychiatric-Mental Health Nurse Practitioner Certificate Program, Department of Nursing, University of New Hampshire, Durham.

Hildegard Peplau: Psychiatric Nurse of the Century

2. D’Antonio P, Beeber L, Sills G, Naegle M. The future in the past: Hildegard Peplau and interpersonal relations in nursing. 

3. Drew BL. The evolution of the role of the psychiatric mental health advanced practice registered nurse in the United States. 

4. American Nurses Credentialing Center. 2017 certification renewal requirements. June 1, 2016. Accessed March 24, 2021. 

https://www.nursingworld.org/~4ac164/globalassets/certification/renewals/RenewalRequirements

5. American Association of Nurse Practitioners. State practice environment. Updated January 1, 2021. Accessed March 24, 2021. 

https://www.aanp.org/advocacy/state/state-practice-environment

6. Massachusetts Coalition of Nurse Practitioners. Massachusetts NPs granted full practice authority! January 1, 2021. Accessed March 24, 2021. 

https://mcnp.enpnetwork.com/nurse-practitioner-news/212292-massachusetts-nps-granted-full-practice-authority-

PMHNPs have years of experience as professional nurses, which serve to hone their clinical judgment and assessment skills.

On Becoming a PMHNP

A report published by the United States Department of Health and Human Services Health Resources and Services Administration projected that the mental health care field will be 

short 250,000 mental health professionals by 2025

 The need is most significant in rural areas, where 111 million Americans currently reside.

 For instance in New Hampshire, where I live and practice, there are significant shortages of psychiatrists and other 

 With the rise in the number of psychiatrists reaching retirement, psychiatric mental health nurse practitioners (PMHNPs) can play an important role in addressing these shortages.

 invited me to be the first nurse practitioner liaison to foster the dialogue between PMHNPs and psychiatrists. Throughout my nursing and PMHNP career, I have benefited from working with exceptional clinicians—PMHNPs, psychiatrists, therapists, and other intradisciplinary team members—and I look forward to further engaging with colleagues in the mental health care field.

My clinical background has primarily been in community mental health center settings, but in the past few years I have transitioned to education as a clinical assistant professor and program director of a post-master’s PMHNP program. In this setting, I have worked with an incredible group of colleagues—psychiatrists and PMHNPs—within my department. The constant interprofessional collaboration to optimize care for a patient population with significant needs has been inspiring.

During my time at a community mental health center, that collaboration proved important. I recall one day when everything that could go wrong did go wrong. The lowest point of the day was when I learned of the death of a patient with whom I had been working for years.

After we receive terrible news like this, we so often have to set aside our grief to continue with our day—see the next patient, finish our documentation, and carry on. Trying to refocus, I marched toward a dreaded peer-to-peer phone call with an insurance reviewer, who was likely not going to approve medication. The patient in question was relatively new to me; he was a young man who, after years of struggling, had finally achieved stability. I was not inclined to change a regimen that was well tolerated and provided remission of symptoms the patient had been experiencing for the majority of his young life.

 against mental illness and patients, there can be stigma against nurse practitioners. I sensed a problem as soon as the call began, and it was clear the reviewer held a negative view of my role. For this patient’s best interest, I realized it was neither the time nor the place to argue the bigger issue. Instead, I explained to the reviewer I was operating within the scope of practice and in congruence with nurse practitioner practice authority in my state. Astonishingly, the reviewer indicated the decision was made to deny the medication for one reason: I was a nurse practitioner. As such, the reviewer added, it was his opinion that my assessment was invalid based on my credentials and could not be used to justify the use of this medication.

I was stunned, speechless, and angry. I understand not everyone will support my professional role, but I would not allow a misunderstanding about scope of practice and this individual’s bias to interfere with appropriate patient care and the patient’s best interest. By denying the medication coverage, they were not hurting me, they were hurting the patient. That was something I could not—and would not—let go.

What was my next stop? I visited my colleague, a psychiatrist. I explained the situation, and he jumped right into action to assist me in achieving a resolution. As it turned out, the previous conversation was recorded; it was clear what had happened. The outcome was the only reasonable one: The patient’s medication was covered for the next few years.

Working in mental health is not the average career in which you go home and share what happened during your workday. Thus, the connections we share with one another as colleagues in a workplace or within the same field are much more meaningful. I have found it rewarding to support not only my patients, but also my colleagues—psychiatrists, nurse practitioners, and other mental health professionals. As John J. Miller, MD, wrote in a 

, we are all part of a team facing the monumental task of meeting the mental health needs of all Americans.

Every PMHNP takes a unique path to the specialized education, training, and subsequent national certification to practice (

). Although our journeys may be different, we value hearing about our psychiatrist colleagues’ experiences. In the community mental health center setting, I enjoyed opportunities for formal and informal supervision with my psychiatrists, and we had been able to support one another throughout work and beyond. Although I no longer work in this position, I remain in contact with both psychiatrist and nurse practitioner colleagues. There is a bond that is difficult to define or put into words. Sharing a purpose and mission of facilitating optimal care for our patients as well as our goals of ongoing learning is part of this camaraderie.

As I greatly value my relationships with my psychiatrist colleagues, I also have found the world of PMHNPs to be incredibly welcoming and supportive. One thing I look forward to (among a lengthy list of other prepandemic activities) is a return to in-person educational conferences, such as that of the American Psychiatric Nurses Association.

If you have the opportunity to meet a PMHNP, whether you are interviewing them for a job or collaborating with them, take a moment to ask them why they pursued this specialty. And please tell us your story, too. Within the current health care climate (and because of the many stresses related to patient acuity, reimbursement, productivity, and prior authorizations), it is refreshing and energizing to talk with each other about why we are here and what led us to this profession. In this manner, we can better appreciate and acknowledge the similarities and differences that led us to care for patients in need of psychiatric care.

Our field promotes and appreciates collaboration and gleaning knowledge from others. I encourage PMHNP students to seek employment with an agency that provides formal supervision, regardless of state-level regulations for practice autonomy. In fact, when I was seeking my first job following PMHNP certification, I only considered positions that offered formal supervision, even though I practiced in an independent-authority state. The position I chose had the best setup for not only formal weekly supervision with a psychiatrist, but also informal open-door consultations with my colleagues at any time. One such colleague was Miller, who is Editor-in-Chief of this publication. I am incredibly lucky to have him as a resource and a mentor, along with the other wonderful clinicians and psychiatrists with whom I have had the opportunity to work.

Learning is a lifelong process, and the ability to continue to be receptive to new information and feedback is crucial for all clinicians. PMHNPs greatly value our collaboration with physicians and appreciate the many psychiatrists who have offered their expertise and time to PMHNP students and PMHNPs in clinical practice via formal or informal collaboration and supervision, mentorship, and support. I have been particularly fortunate to work with supportive psychiatrists over the years, some of whom remain close friends.

 team and look forward to providing an avenue for the voice of fellow nurse practitioners. Many PMHNPs and psychiatrists are already collaborating well, but I hope to facilitate even more nurse practitioner contributions and PMHNP-psychiatrist partnerships. Here’s to the start of more beautiful collaborations.

is a psychiatric mental health nurse practitioner in the Seacoast, New Hampshire, area and clinical assistant professor and program director of the Post-Masters Psychiatric-Mental Health Nurse Practitioner Certificate Program, Department of Nursing, University of New Hampshire, Durham.

1. US Department of Health and Human Services; Health Resources and Services Administration, Bureau of Health Workforce; National Center for Health Workforce Analysis. National projections of supply and demand for behavioral health practitioners: 2013-2025. November 2016. Accessed March 24, 2021. 

https://bhw.hrsa.gov/sites/default/files/bureau-health-workforce/data-research/behavioral-health-2013-2025.pdf

2. New Hampshire Department of Health and Human Services. New Hampshire 10-year mental health plan. January 2019. Accessed March 24, 2021. 

https://www.dhhs.nh.gov/dcbcs/bbh/documents/10-year-mh-plan.pdf

3. Yang BK, Trinkoff AM, Zito JM, et al. Nurse practitioner independent practice authority and mental health service delivery in U.S. community health centers. 

4. Miller JJ. Psychiatry 2021: team psychiatry. 

We are all part of a team facing the monumental task of meeting the mental health needs of all Americans.

Partnering for the Greater Good

, by John J. Miller, MD, editor in chief of 

Psychiatrists and mental health nurse practitioners should be natural allies. Unfortunately, national initiatives and some agencies have encouraged an us vs them mentality, pitting psychiatrists against nurse practitioners and other advanced care providers. Competitive language is hurtful and, worse, counterproductive to good care. Psychiatric-Mental Health Nurse Practitioners (PMHNPs) and psychiatrists share the goal of caring for patients in need of psychiatric treatment. It is important to appreciate nuances and recognizing that training, degree, or certification alone does not translate to a good provider. It is a great task to meet the mental health needs of Americans, and we all can play important roles and support each other in this vital mission

PMHNPs can play a critical role in addressing shortages of mental health providers.

 A report published by the United States Department of Health and Human Services Health Resources and Services Administration projects that the mental health field will be 

 The need is most significant in rural areas, where 111 million Americans currently reside—areas without sufficient mental health professionals.

 In states with independent practice authority for nurse practitioners, such as New Hampshire, PMHNPs are able to provide significantly more mental health services when compared with nurse practitioners (NPs) who practice in states without 

Psychiatry-mental health is one of the fastest growing, non-physician specialties in the 

 In my experience, PMHNPs greatly value working as a team with our colleagues within the field—psychiatrists, clinical psychologists, therapists, etc. We greatly value our collaboration with physicians and appreciate the many psychiatrists who have offered their expertise and time to PMHNP students by precepting, and with PMHNPs in clinical practice via formal or informal collaboration, along with supervision, mentorship, and support. A holistic, patient-centered approach translates favorably to patient outcomes and collaboration.

In fact, patients report favorable experiences working with nurse practitioners.

 Findings from the Kippenbrock et al study determined that patients had greater satisfaction with their care provided by nurse practitioners when compared with their MD colleagues.

 A systematic review by Stanik-Hutt et al evaluated published literature over a period of 19 years and evaluated quality, safety, and effectiveness of care provided by Masters-prepared nurse practitioners.

 Investigators found that patient outcomes from nurse practitioners working independently or with MD collaboration had similar outcomes, when compared with the patients working with MDs alone.

Every PMHNP has a unique journey leading them to pursuing the specialized education, training and subsequent national certification to practice. Nurse practitioner practice authority varies from state to state, with variations of full practice, reduced practice, and 

 Many states require collaboration with a physician for nurse practitioners to practice. Advocacy for expanding the role of the nurse practitioner is continually occurring on a state level. Massachusetts recently joined the rest of the New England states by passing legislation to grant nurse practitioners full practice authority.

 This made Massachusetts the 23rd state to pass full practice authority for nurse practitioners.

PMHNPs can provide excellent care due to their extensive education and training. They are first and foremost Registered Nurses (RNs). The advanced practice, masters-prepared role for nurses was first the Clinical Nurse Specialist, and later shifted to the Advanced Practice Registered Nurse (APRN) in the early 1990s.

 Today, once they have obtained RN licensure, RNs are eligible to pursue further degrees on both a Masters and Doctoral level.

In addition to nurse practitioner role courses, advanced pathophysiology, pharmacology, and health assessment courses, PMHNPs complete intensive coursework and clinical practicum experiences. Students obtain 500-1000 clinical hours and complete coursework in neurobiology, psychotherapeutic modalities, differential diagnosis, and psychopharmacology. Change is on the horizon in nursing education, as the plan to transition into doctoral-level education for all nurse practitioners is in the pipeline. This is important to align advanced practice nurses with our colleagues in other professions that have also shifted to doctoral-level preparation. Nurse practitioner students will obtain additional clinical hours along with added coursework, further preparing nurses as advanced practice clinicians and health care leaders.

Upon completion of an accredited program, students are eligible to sit for the board certification exam through American Nurses Credentialing Center (ANCC) to obtain PMHNP certification. Board-certified PMHNPs are required to renew national certification every 5 years and must complete 75 continuing education units (CEUs) along with additional tasks to meet criteria for maintaining certification. Nurse practitioners maintain certification renewal by completing requirements and engaging in ongoing efforts to pursue education, in 

 Additionally, all PMHNPs must meet specific state-level requirements for maintaining state licensure as both an RN and an NP, and many states require renewal of these licenses every 2 years.

As a PMHNP for 6 years, I have had the pleasure of working with many incredible patients and clinicians. In this vein, I am thrilled to be the first Nurse Practitioner Liaison for 

. My fellow PMHNPs and I leverage our nursing background and complement it with the art and science of psychiatry to provide patients with evidence-based, sound clinical care. And we are glad to work together with you.

As the liaison, I look forward to sharing stories, exchanging perspectives, and helping each other meet the noble goal of addressing the mental health needs of Americans. Within the current health care climate and many stresses related to patient acuity, reimbursement, productivity, and prior authorizations, it is refreshing and energizing to talk to each other about why we are here, and what led us to this profession. Comments and suggestions for articles are welcomed and can be sent to 

 is a psychiatric-mental health nurse practitioner in the Seacoast, New Hampshire area; and clinical assistant professor & program director of the Post-Masters Psychiatric-Mental Health Nurse Practitioner Certificate Program, Department of Nursing, University of New Hampshire, Durham, NH.

1. Yang BK, Trinkoff AM, Zito JM, et al. Nurse practitioner independent practice authority and mental health service delivery in US community health centers. 

2. US Department of Health and Human Services. Health Resources and Services Administration, Bureau of Health Workforce. National Projections of Supply and Demand for Behavioral Health Practitioners: 2013-2025. November 2016. Accessed January 25, 2021. 

3. New Hampshire Department of Health and Human Services: Bureau of Behavioral Health New Hampshire 10-year mental health plan

 January 2019. Accessed January 25, 2021. 

4. Massachusetts Coalition of Nurse Practitioners. Massachusetts NPs granted full practice authority! Published January 1, 2021. Accessed January 25, 2021. 

5. American Psychiatric Nurses Association. Expanding mental health care services in America: the pivotal role of psychiatric-mental health nurses. April 2019. Accessed January 25, 2021. 

https://www.apna.org/files/public/Resources/Expanding_Mental_Health_Care_Services_in_America-The_Pivotal_Role_of_Psychiatric-Mental_Health_Nurses_04_19.pdf

6. Kippenbrock T, Emory J, Lee P, et al. A national survey of nurse practitioners' patient satisfaction outcomes. 

7. Stanik-Hutt, J, Newhouse RP, White KM, et al. The quality and effectiveness of care provided by nurse practitioners. 

8. American Association of Nurse Practitioners. State practice environment. January 1, 2021. Accessed January 25, 2021. 

9. Drew BL. The evolution of the role of the psychiatric mental health advanced practice registered nurse in the United States. 

10. American Nurses Credentialing Center. 2017 certification renewal requirements. June 1, 2016. Accessed January 25, 2021. 

The shortage of mental health care providers is a crisis, but psychiatrists have a potentially powerful ally. 

Partnering With Psychiatric-Mental Health Nurse Practitioners

L-methylfolate is commonly presented as a safe augmenting agent to patients with antidepressant non-response in unipolar depression with virtually no side effects. Although this is likely to be true most of the time, as with any treatment, there are risks that can be significant albeit rare. Currently, there is a paucity of published literature of double-blind placebo-controlled randomized clinical trials of the efficacy and tolerability of L-methylfolate in both unipolar and bipolar depression. This article discusses the rationale and history of L-methylfolate use in such patients, and then shares three cases that collectively suggest L-methylfolate may contribute to agitation and mania.

In humans, folate (ie, Vitamin B9) is one of 13 essential vitamins. Low serum folate and low red blood cell (RBC) folate levels are independent risk factors for major depressive disorder (MDD); they also are associated with more 

 Maternal folate deficiency prior to conception and throughout pregnancy has been 

to increase the risk of neural tube defects and congenital abnormalities in the developing fetus, as well as peripheral neuropathy and anemia in the mother.

Ongoing studies in psychiatry and obstetrics support the use of oral dosing with the bioactive form of folate, L-methylfolate. L-methylfolate is FDA approved as a medicinal supplement for 

 The use of L-methylfolate allows the clinician to bypass a critical metabolic step in folate’s transformation to L-methylfolate, specifically the reduction of methylenetetrahydrofolate to L-methylfolate by the enzyme methylenetetrahydrofolate reductase (MTHFR). MTHFR is the rate limiting step in this process, and significantly, MTHFR enzymatic activity has a wide range of function depending on its genetic polymorphisms at three nucleic acid sites, the most significant being: C677C (good activity), C677T (decreased activity), and T677T (poor activity).

L-methylfolate is the only form of folate that can cross the blood-brain barrier, where it plays an essential role in the one carbon cycle metabolic pathway that is 

for the production of the monoamines serotonin, dopamine, and norepinephrine.

 undertook a randomized study of L-methylfolate as adjunctive therapy in patients with MDD who had a partial response or no response to selective serotonin reuptake inhibitors. A population of 75 patients were treated for 60 days with 15 mg L-methylfolate daily. The findings indicate that L-methylfolate was significantly more effective as compared with placebo. The response rates were 32.3% in the SSRI plus 15 mg L-methylfolate group compared with 14.6% in the SSRI plus placebo group.

The number needed to treat to achieve response with the addition of 15 mg L-methylfolate to an SSRI was 6. Overall L-methylfolate was well tolerated with minimal adverse effects; manic symptoms developed in one patient in the L-methylfolate/SSRI group, which resulted in patient discontinuation.

A subset of the original acute treatment cohort was followed in a 12-month open-label continuation 

 during which outpatients were treated with 15 mg L-methylfolate and an SSRI.

 The researchers reported “high rates of response, remission, and recovery,” as well as overall safety, tolerability, and a good rate of retention.

Unfortunately, there is a paucity of research into the use of L-methylfolate to treat bipolar I depression (BD-I). To address this unmet need, 

 created an open label registry of patients with bipolar depression. The patients received treatment as usual as well as 15 mg L-methylfolate daily for 6 weeks. Pre-study medications included lithium, lamotrigine, quetiapine, valproate, lurasidone, levothyroxine, Dexedrine, and extended release methylphenidate. At week 6, there was a 50% or greater improvement on the Montgomery Asberg Depression Rating Scale, with a pre-treatment mean score of 23.4 and a post-treatment score of 13.9 in six of the 10 patients studied. Significantly, the researchers noted that one patient had “an exacerbation in YMRS (Young Mania Rating Scale) and a possible manic episode.”

With that in mind, we present three case vignettes of women with affective disorders, two with MDD and one with BD-I. All three had acute symptoms of agitation shortly after augmenting their divergent psychotropic medication regimen with 15 mg of L-methylfolate. In all 3 cases, the agitation rapidly improved upon discontinuation of L-methylfolate.

“Jesse” was a 63-year-old married white woman who was on disability for multiple sclerosis. She struggled with treatment-resistant MDD for several years, with no evidence of a bipolar diathesis. She received numerous antidepressant medication trials, including therapeutic doses of phenelzine, fluoxetine, sertraline, nortriptyline, escitalopram, mirtazapine, venlafaxine, vilazodone, vortioxetine, and duloxetine; all of which failed.

Pharmacogenomic testing of the MTHFR gene was consistent with decreased activity of this enzyme (C677T). It was decided to augment duloxetine with 15 mg L-methylfolate daily.

After several days on this regimen, her husband called to report that she had become uncharacteristically irritable and agitated. No identifiable situational stressors, substance use, new medication, or medical illness could be identified. Her long-term medical history was significant for multiple sclerosis, hyperlipidemia, osteoporosis, neurogenic bladder, and hypertension.

Shortly after discontinuing the L-methylfolate, the irritability and agitation resolved. Upon obtaining further history, the patient reported a hypomanic-like adverse effect from previous prednisone treatment. There was no other history of bipolar spectrum symptoms.

“Leslie” was a 43-year-old married white woman who presented with a history of treatment-resistant MDD with multiple antidepressant failures. The trials included imipramine, paroxetine, sertraline, escitalopram, duloxetine, venlafaxine, and fluoxetine. Her medical history was significant for multiple sclerosis, asthma, and migraines. She was taking venlafaxine XR 225 mg for an adequate duration, but there was a suboptimal response of her depressive symptoms when the 15 mg L-methylfolate daily was added. Upon follow up six weeks later, she reported that her experience with the L-methylfolate was horrible, describing herself as feeling “agitated and aggressive.”

“Susan” was a 56-year-old divorced white mother with a longstanding history of bipolar disorder who presented with an episode of depression. She had had previous episodes of mania, complicated mania with psychosis, and depression as well as several inpatient psychiatric hospitalizations for repeated manic episodes and psychotic symptoms; her most recent hospitalization was more than 15 years prior to the current episode of depression. Over the previous several years, her symptoms were reasonably well-managed on a combination of carbamazepine and oral/depo injection haloperidol. Chronic residual symptoms included a notably flat affect, anhedonia, and a largely depressed mood at baseline.

Pharmacogenomic testing was performed as part of her work up, and it revealed that her MTHFR gene tested homozygous (T677T), which suggested poor enzymic activity. A trial of 15 mg L-methylfolate daily was initiated to target recalcitrant depressive symptoms.

The patient called a few days after L-methylfolate initiation and described feeling unwell, agitated, and seeming to be a bit paranoid. She was instructed to discontinue the L-methylfolate, and these symptoms resolved within a few days. She reported that she quickly felt more like herself after discontinuing the L-methylfolate. She described the brief trial as horrible and stated that she “will never take it (L-methylfolate) again.”

These case vignettes suggest that patients with unipolar or bipolar depression may be at risk for the onset of agitation shortly after beginning a trial of 15 mg L-methylfolate. In all three cases, the agitation resolved a few days after discontinuing the L-methylfolate, supporting the likelihood that it contributed to the agitation. It is interesting to note that the two patients with MDD both had a comorbid diagnosis of multiple sclerosis. This, however, may very well be coincidental.

The findings presented are preliminary and are presented with the aim of raising clinicians’ awareness that L-methylfolate may contribute to symptoms of agitation, irritability, and possibly hypomania, mixed mania, or mania in susceptible individuals. The only concrete conclusion that can be drawn is that well-designed clinical trials are needed to ferret out the rare but potentially significant adverse events associated with L-methylfolate.

There are no clinical data on the risks/benefits/adverse effects of the use of L-methylfolate off label in the treatment of bipolar depression. This is a significant lack of information, because many patients who ultimately have a diagnosis of bipolar disorder are initially treated-sometimes for years and even decades-for unipolar depression. The study by 

 demonstrated that 7.5 mg of L-methylfolate performed no better than placebo as an augmentation agent in patients with MDD who did not respond to SSRIs, whereas 15 mg per day of L-methylfolate significantly separated from placebo. The dose response of L-methylfolate for effectiveness and adverse events in BD-I is unknown.

Future studies to assess the clinical consequences of augmenting antidepressants with L-methylfolate should include:

1. Large placebo controlled clinical trials

 of both unipolar depression and bipolar depression to determine the number needed to harm in the different patient populations, as well as the number needed to treat in bipolar patients.

2. Augmentation of non-SSRI antidepressants

 with L-methylfolate to determine if the improvement seen in MDD when SSRIs are augmented with L-methylfolate are generalizable to all antidepressants.

3. An evaluation of the L-methylfolate dosage range

 in patients with bipolar depression to determine which dosages (3.75 mg, 7.5 mg, 15 mg) are helpful and which are harmful.

These three cases illustrate the rare but possible adverse effects of agitation, irritability and possible onset of hypomania with adjunctive L-methylfolate. The publications reviewed report one patient who developed manic symptoms while taking L-methylfolate/SSRI for unipolar depression,

 and one patient who developed an increase in the YMRS and a possible manic episode when L-methylfolate was added to the regimen treating the underlying bipolar disorder.

 This activation by L-methylfolate is consistent with its putative mechanism of action, specifically increasing brain levels of norepinephrine, dopamine, and serotonin.

L-methylfolate, the bioactive form of folate that crosses the blood-brain barrier, has been shown to effectively augment SSRIs in patients with MDD who did not respond to SSRI monotherapy; and it also has been shown to be generally well tolerated. Its role in augmentation in bipolar depression remains to be determined. Although the current data are limited, clinicians and patients should be aware of the possibility that L-methylfolate may increase agitation and may contribute to the onset of hypomania/mania.

 is Psychiatric-Mental Health Nurse Practitioner, Seacoast Mental Health Center, Portsmouth, NH; and Clinical Assistant Professor, Department of Nursing, University of New Hampshire, Durham, NH; 

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

 Staff Psychiatrist, Seacoast Mental Health Center, Exeter, NH; Consulting Psychiatrist, Exeter Hospital, Exeter, NH; and Consulting Psychiatrist, Insight Meditation Society, Barre, MA. Ms. Robinson and Dr Miller indicate they have nothing to disclose regarding the subject of this article.

1. Papakostas GI, Cassiello CF, Iovieno N. 

Folates and S-adenosylmethionine for major depressive disorder

2. Alpert JE, Mischoulon D, Nierenberg AA, Fava M. 

Nutrition and depression: focus on folate

Folic acid supplementation and pregnancy: more than just neural tube defect prevention

Treatment-resistant depression: recent developments and future directions

5. Stahl SM. Novel therapeutics for depression: L-methylfolate as a trimonoamine modulator and antidepressant-augmenting agent. 

6. Papakostas GI, Shelton RC, Zajecka JM, et al. 

L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials

7. Zajecka JM, Fava M, Shelton RC, et al. 

Long-term efficacy, safety, and tolerability of L-methylfolate calcium 15 mg as adjunctive therapy with selective serotonin reuptake inhibitors: a 12-month, open-label study following a placebo-controlled acute study

8. Nierenberg AA, Montana R, Kinrys G, et al. 

L-Methylfolate for bipolar I depressive episodes: an open trial proof-of-concept registry