WINTER 2021 | VOLUME 19 | NUMBER 1

PSYCHOPHARMACOLOGY

Focus
The Journal of Lifelong Learning in Psychiatry
WIN TER 2021 | VOLUME 19 | NUMBER 1

Perspectives in Psychopharmacology
Guest Editor: Boadie W. Dunlop, M.D., MSCR
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Focus VOLUME 19 • NUMBER 1 • WINTER 2021

FROM THE GUEST EDITOR

1 Navigating the Novel Psychotropics

Boadie W. Dunlop, M.D., MSCR

FEATURES

REVIEW
3 Contrasting Typical and Atypical Antipsychotic Drugs
Herbert Y. Meltzer, M.D., and Erick Gadaleta, D.O.

CLINICAL SYNTHESIS
14 Tardive Dyskinesia: Spotlight on Current Approaches to Treatment
Sarah M. Debrey, M.D., and David R. Goldsmith, M.D.
The current pharmacological options, especially with the more widespread use of the VMAT2 inhibitors,
offer some hope for greater symptomatic improvement that may lead to greater quality of life and
recovery for patients.

24 Increasing Psychiatrists’ Role in Addressing the Cardiovascular Health of Patients With

Severe Mental Illness
Martha Ward, M.D.
Cardiovascular disease is the leading cause of death for people with serious mental illness. Psychiatrists
are well situated to address their patients’ holistic health and must stand up as leaders in prioritizing the
overall health of people with serious mental illness.

31 Novel Formulations of ADHD Medications: Stimulant Selection and Management

Ann C. Childress, M.D.
About 30 different amphetamine and methylphenidate formulations, including immediate- and extended-
release compounds, are now approved to treat ADHD. To select the right one for a patient, depends on
understanding a drug’s pharmacokinetic and pharmacodynamic profiles, as well as other key factors.

39 Treatment of Hypoactive Sexual Desire Disorder Among Women: General Considerations

and Pharmacological Options
Gabriela S. Pachano Pesantez, M.D., and Anita H. Clayton, M.D.
The authors discuss the diagnostic tools available for hypoactive sexual desire disorder (HSDD) and
general diagnostic considerations for psychiatrists. They also review the pathophysiology behind HSDD
and emphasize the treatment of HSDD, including treatment with psychotherapy and medications.

46 Innovations in Psychopharmacology Education in U.S. Psychiatric Residency Programs

Jeffrey Rakofsky, M.D.
Innovations have increased in the areas of psychopharmacology curricula topics, teaching strategies, and
knowledge and skill assessments. Psychiatric training programs can benefit from these innovations,
ensuring that all graduating physicians meet learning objectives that can be reliably measured.

ASK THE EXPERT

50 Moving on With Monoamine Oxidase Inhibitors
J. Alexander Bodkin, M.D., and Boadie W. Dunlop, M.D.
ETHICS COMMENTARY
53 Ethical Issues in Psychopharmacology
Nataly S. Beck, M.D., et al.

21ST-CENTURY PSYCHIATRIST
59 COVID-19 and the Doctor-Patient Relationship
David C. Fipps, D.O., and Elisabet Rainey, M.D.

61 Integrating Diversity, Equity, and Inclusion Into an Academic Department of

Psychiatry and Behavioral Sciences
Nadine J. Kaslow, Ph.D., et al.

APPLIED ARMAMENTARIUM
66 Never Say Never: Successful Clozapine Rechallenge After Multiple Episodes
of Neutropenia
Michael Shuman, Pharm.D., et al.

INFLUENTIAL PUBLICATIONS

71 Bibliography

73 Abstracts

76 Combinatorial Pharmacogenomic Testing Improves Outcomes for Older Adults With

Depression
Brent P. Forester, M.D., M.S.c., et al.

86 Mortality Risk of Antipsychotic Augmentation for Adult Depression

Tobias Gerhard, et al.

95 Psychedelics and Psychedelic-Assisted Psychotherapy

Collin M. Reiff, M.D., et al.

116 The Impact of Pharmacological and Non-Pharmacological Interventions to Improve

Physical Health Outcomes in People With Schizophrenia: A Meta-Review of
Meta-Analyses of Randomized Controlled Trials
Davy Vancampfort, et al.

129 Safety and Efficacy of Adjunctive Second-Generation Antidepressant Therapy With

A Mood Stabiliser or an Atypical Antipsychotic in Acute Bipolar Depression:
Randomised Systematic Review and Meta-Analysis of A Placebo-Controlled Trials
Alexander McGirr, et al.

DEPARTMENTS

45 Call for Papers: The Applied Armamentarium

58 Call for Papers

65 Call for Papers: 21st-Century Psychiatrist

138 Continuing Medical Education

October 15, 1970: Dr. Julius Axelrod poses in his laboratory at the
National Institute of Mental Health after the announcement that he had
won the Nobel Prize for Medicine. He described his prize-winning work
as a long-time study of how nerves transmit messages to body organs.
“This can lead to a better understanding of suitable drugs and treatment
for some illnesses.” (Photo credit: Bettmann, Getty Images)

Navigating the Novel Psychotropics
A decade ago, psychiatry was awash with pessimistic pre-
dictions about the future of pharmacotherapy for mental
illnesses. With too many potential targets and no coherent
pathophysiological models, “Big Pharma” was pulling in its
sails, giving up on neuropsychiatric drug discovery (1). Psy-
chiatrists and patients were going to be stuck with the same
old drugs for a long time to come.
What a difference a decade makes. The recent pace of
discovery has left many clinicians feeling a bit at sea, strug-
gling to keep up with developments across the pharmacopeia.
Over the past 5 years, entirely new classes of medications have
been marketed in psychiatry, targeting glutamate, neuro-
steroid, melanocortin, and orexin receptors, as well as ve-
sicular transporters. Other developments include numerous
new formulations of medications that alter absorption pro-
files and effective half-lives (2, 3), prodrugs, psychedelic-
and MDMA-assisted psychotherapy, and pharmacogenomic
decision support tools. All of these innovations make dis-
cussion of monoamine transporters and receptors seem old
hat, almost as much as talking about monoamine oxidase
inhibitors (MAOIs) and barbiturates did 20 years ago.
This issue of Focus aims to chart a course through these
pharmaceutical currents. Our lead article, by Herman Meltzer,
M.D., and Erick Gadaleta, D.O., is a tour de force conceptu-
alization of the marketed antipsychotics (4). By combining
pharmacodynamic principles with important take-aways from
antipsychotic clinical trials, Dr. Meltzer challenges us to re-
think our understanding of the utility of the various atypical
antipsychotics and potential approaches to treatment-resistant
schizophrenia. The richness of Dr. Meltzer’s review provides
insights that emerge beyond one’s initial reading of the text;
this is an article that rewards clinicians the more deeply they
engage with it.
An unfortunate consequence of antipsychotic treatment,
tardive dyskinesia (TD) has recently acquired new promise
in the form of the reversible vesicular monoamine transporter-
2 (VMAT-2) inhibitors. Although tetrabenazine has been
available for decades, pharmacokinetic factors have limited
its clinical application for TD. Drs. Sarah Debrey and David
Goldsmith (5) provide a thorough review of the pharmacology
and clinical utility of deutetrabenazine and valbenazine, two
newly marketed VMAT-2 inhibitors. The authors also discuss
how these newer agents are important developments in our
long battle against TD, and their position relative to the old
standby clozapine and the novel approaches of neurostimulation.
Clinicians treating patients who have received antipsychotics
will be well informed by this outstanding review.
Focus Vol. 19, No. 1, Winter 2021
FROM THE GUEST EDITOR
Metabolic disruptions and their consequences are another
unhappy complication of antipsychotic treatment and reduce
both lifespan and quality of life. Cardiovascular diseases are
common comorbidities among psychiatric patients, who may
be unwilling or unable to obtain primary care treatment. For
such patients, mental health clinicians need to take an active
role in monitoring and addressing these problems. In her over-
view, Dr. Martha Ward (6) provides a very practical and
impactful approach that mental health clinicians can easily apply
to improve the cardiovascular health of their patients. First-step
interventions such as metformin to address glucose dysregula-
tion and tobacco addiction treatments are aspects of patient care
that psychiatrists ought to become comfortable with, consid-
ering the fractured nature of health care in the United States.
Sexual dysfunction, particularly hypoactive sexual desire
disorder (HSDD), is a significant contributor to reduced quality
of life and relationship stress. Drs. Gabriela Pachano Pesantez
and Anita Clayton (7) provide a review of the diagnostic con-
siderations and treatment options for this common and
challenging-to-treat condition. Flibanserin and bremelano-
tide are two newly marketed medications for HSDD, which
possess unique pharmacodynamic actions and issues related
to tolerability. This article will help guide clinicians in the
use of these new agents vis-à-vis other potential interven-
tions, such as testosterone or psychotherapy.
In the realm of attention-deficit hyperactivity disorder, it
hasn’t been the emergence of new mechanisms but rather
the astonishing number of new formulations that challenge
clinicians’ pharmacological competence. Erupting like so
many flittering flying fish, transiently capturing our atten-
tion before disappearing again beneath the relentless flow of
information, the novel stimulant formulations have clinical
utilities and differentiating characteristics that may be hard
for prescribers to retain in memory. Dr. Ann Childress (8)
provides a structured approach for thinking through these
new formulations and their pharmacokinetically-driven
clinical applications. The generic names for these various
reformulations are highly overlapping and make retention
by the clinician even more challenging; thus, for this article,
we have deviated from our usual practice and permitted the
use of branded drug names for clarity.
As pharmacologic complexity increases in psychiatry, it
seems clear that residency training programs are going to
need to commit even more time and expertise to psycho-
pharmacology education. Dr. Jeffrey Rakofsky (9) reviews
the advances made to date in this area, including novel uses
of technologies and supervision methods. Interactive
focus.psychiatryonline.org 1
FROM THE GUEST EDITOR
teaching, in which the learner is required to think through
the pros and cons of applying specific medications to specific
patients will need to become a bigger part of the learning
process. Currently, trainees usually learn about medications
in the abstract and then at some later date attempt to recall
that information as they haphazardly encounter patients for
whom it is applicable. Greater learning consolidation could
be achieved if, shortly after participating in didactic instruction
around the theoretical aspects of pharmacology, trainees en-
gaged in computerized simulations programmed for the ap-
plication of recently acquired drug knowledge. Trainees also
need to understand the importance of committing to lifelong
learning focused on updating and reinforcing one’s knowledge
in psychopharmacology, through “learning how to learn” on
one’s own. We must instill in our trainees how to actively and
thoughtfully approach claims about the efficacy, safety, mech-
anism, and metabolism of new medications, for the pace of
discovery is unlikely to slow.
Our Ask the Expert column (10), coauthored by Dr.
Alexander Bodkin and me, provides a throwback amid this
exciting rush of new medications and their associated mecha-
nisms. By offering an approach for clinicians to go “backwards”
from current, often multidrug, regimens to the old mechanism
of monoamine oxidase inhibition, this column reminds us that
newer does not automatically equate to better. Sure, it would be
easier if we did not have to think about MAOIs anymore, given
all their interactions and potential for serious adverse reactions.
We could commit our pharmacologic learning efforts to the
newer, safer, and easier-to-use medicines. But the successful
MAOI treatment of just one patient who has failed numerous
other drug mechanisms can reveal the value in knowing and
retaining as much pharmacologic knowledge as possible. Until
these disorders that plague our patients can be distilled to their
underlying pathophysiology, accompanied by targeted thera-
peutics that reverse that pathophysiology, we are going to need
all our tools to optimize our patients’ outcomes.
Conclusion
To perceive accurately, to reason sensibly, to feel rightly, and
to act purposefully, aligned with one’s truest sense of self.
2 focus.psychiatryonline.org
This is the goal of mental health treatment, and for many
patients psychopharmacology is an indispensable support
for that journey. To best aid our patients, we must work
continually to deepen our knowledge of our medicines, in-
cluding their mechanisms, kinetics, interactions, harms, and
comparative advantages. There is no shortcut to possessing
such knowledge; it is acquired only through study and
practice. Our patients look to us for this expertise. As
physicians, understanding to the fullest of our ability the
workings of the chemicals we prescribe is a moral impera-
tive. This issue of Focus aims to support your growth as a
psychopharmacologist, and I hope you come away enriched
for engaging with the knowledge contained within.
REFERENCES
1. Miller G: Is pharma running out of brainy ideas? Science 2010; 329:
502–504
2. Andrade C: Sustained-release, extended-release, and other time-
release formulations in neuropsychiatry. J Clin Psychiatry 2015; 76:
e995–e999
3. Boxenbaum H, Battle M: Effective half-life in clinical pharmacol-
ogy. J Clin Pharmacol 1995; 35:763–766
4. Meltzer HY, Gadaleta E: Contrasting typical and atypical antipsy-
chotic drugs. Focus 2021; 19:3–13
5. Debrey SM, Goldsmith DR: Tardive dyskinesia: spotlight on cur-
rent approaches to treatment.Focus 2021; 19:14–23
6. Ward M: Increasing psychiatrists’ role in addressing the cardio-
vascular health of patients with severe mental illness. Focus 2021;
19:24–30
7. Pachano Pesantez GS, Clayton AH: Treatment of hypoactive sexual
desire disorder among women: general considerations and phar-
macological options. Focus 2021; 19:39–45
8. Childress AC: Novel formulations of ADHD medications: stimulant
selection and management. Focus 2021; 19:31–38
9. Rakofsky J: Innovations in psychopharmacology education in US
psychiatric residency programs. Focus 2021; 19:46–49
10. Bodkin JA, Dunlop BW: Moving on with monoamine oxidase in-
hibitors. Focus 2021; 19:50–52
Boadie W. Dunlop, M.D., MSCR
Department of Psychiatry and Behavioral Sciences and Mood and Anxiety
Disorders Program, Emory University School of Medicine, Atlanta. Send
correspondence to Dr. Dunlop (bdunlop@emory.edu).
Received and accepted October 30, 2020.
Focus 2021; 19:1–2; doi: 10.1176/appi.focus.20200044
Focus Vol. 19, No. 1, Winter 2021

Contrasting Typical and Atypical Antipsychotic Drugs
Herbert Y. Meltzer, M.D., and Erick Gadaleta, D.O.
The beliefs that antipsychotic drugs (APDs) are 1) effective only
to treat delusions and hallucinations (positive symptoms), 2)
that typical and atypical APDs differ only in ability to cause
extrapyramidal side effects, and 3) that their efficacy as
antipsychotics is due solely to their dopamine D2 receptor
blockade are outmoded concepts that prevent clinicians from
achieving optimal clinical results when prescribing an APD.
Atypical APDs are often more effective than typical APDs in
treating negative symptoms, cognitive impairment, and mood
symptoms as well as reducing the risk for suicide and
decreasing aggression. This applies not only to those
diagnosed with schizophrenia or schizoaffective disorder
but also to bipolar disorder, major depression, and other
psychiatric diagnoses. The greater advantage of an atypical
APD is not evident in all patients for every atypical APD due, in
part, to individual differences in genetic and epigenetic
endowment and differences in the pharmacology of the
atypical APDs, their mode of action being far more complex
than that of the typical APDs. A common misconception is
The goal of this contribution is to provide a clinically useful
guide to antipsychotic drugs (APDs) based on clinical evi-
dence and mechanism of action. It emphasizes the choice of,
and optimal use of, an APD based on receptor profiles,
preclinical studies, and proven actions. The main focus is on
their use in schizophrenia. Much of what has been learned
about their efficacy, side effects, and mechanism of action is
relevant to their uses in other psychiatric disorders. The
results from meta-analyses are not prioritized as they are in
other reviews (1–4), as the emphasis here is to alert the
reader to clinically relevant information that may be helpful
for specific patients, which as meta-analysts note is difficult
to discern in meta-analysis (4). The dichotomization of the
antipsychotics into atypical versus typical classes is the key
organizing principle for this article. It was first proposed in
the 1960s based on the minimal motor side effects of clo-
zapine, the prototypical atypical APD, to contrast it with
chlorpromazine, the prototypical typical antipsychotic and
other APDs with similar functionality. This simple classifi-
cation had, and still has, merit; however, it is misleading, not
only to clinicians but also to basic scientists, who may be
unaware of the important differences in efficacy, side effects,
and mechanisms of action that differentiate the diverse
group of atypical APDs from one another. Powerful voices
have minimized the differences between typical and atypical
Focus Vol. 19, No. 1, Winter 2021
REVIEW
that among the atypical APDs, only clozapine is effective for
reducing psychosis in treatment-resistant schizophrenia.
Aripiprazole, lurasidone, olanzapine, and risperidone also
can be more effective than typical APDs for treatment-
resistant schizophrenia; clozapine is uniquely indicated for
reducing the risk for suicide. The ability of the atypical APDs to
improve cognition and negative symptoms in some patients
together with lower propensity to cause tardive dyskinesia
(an underappreciated advantage) leads to better overall
outcomes. These advantages of the atypical APDs in efficacy
and safety are due, in part, to initiation of synaptic plasticity via
direct and indirect effects of the atypical APDs on a variety of
proteins, especially G proteins, and release of neurotrophins
(e.g., brain-derived neurotrophic factor). The typical APDs
beneficial effects on psychosis are mainly the result of D2
receptor blockade, which can be associated with serious side
effects and lack of tolerability.
Focus 2021; 19:3–13; doi: 10.1176/appi.focus.20200051
APDs, often referring to them as first- and second-generation
APDs (5). The goal here is to highlight important differences
that should inform clinical practice. The pharmacologic basis
for the differential ability of the atypical APDs to improve
psychosis, negative symptoms, and cognitive impairment is
discussed throughout, particularly cognition, because it is so
critical for achieving good outcomes and because there is so
much misinformation about the effect of APDs on cognition.
Table 1 highlights the receptor profiles of the typical and
atypical APDs.
The relevance of these diverse receptor profiles, with an
emphasis on dopamine and serotonin, for the clinical dif-
ferences between typical and atypical APDs has been dis-
cussed in more detail elsewhere (6–9). The main inhibitory
neurotransmitters in the brain are GABA, glycine, and ser-
ine. It is likely that these three neurotransmitters are highly
significant for the pathophysiology of schizophrenia and
other neuropsychiatric disorders and greatly influence the
actions of APDs. Only brief discussion of the potential to
treat schizophrenia with drugs influencing these neuro-
transmitters could be included here. Drugs targeting these
systems will likely come to the fore in the near future.
Similarly, relatively little attention is given to pharmacoge-
nomic studies that can inform choice of medications. Such
studies, as well as other types of biomarkers, can ultimately
focus.psychiatryonline.org 3
CONTRASTING TYPICAL AND ATYPICAL ANTIPSYCHOTICS

TABLE 1. Receptor Affinity Values (Ki) for Atypical and Typical Antipsychotic Drugsa
Receptor
Drug Name D1 D2 D3 5-HT1A 5-HT2A 5-HT2C a2 H–1 M–1
Amisulpride .10K 3 2.4 .10K 8,304 .10K 1,114 .10K .10K
Aripiprazole 387 0.95 5.35 5.6 4.6 181 74 29 .6K
Asenapine NA 2 NA 15 0.8 0.3 16.1 9.3 24.3
Brexpiprazole NA 0.3 1.1 0.1 0.5 0.6 19 negligible
Cariprazine NA 9.2 0.085 8.6 7.7 6.9 ,6.0 7.6 negligible
Chlorpromazine 112 2 4.65 .3K 3.2 26 184 0.18 47
Clozapine 189 431 240 105 13 29 142 2 14
Fluphenazine 21 0.54 1.75 145 7.4 418 314 7.3 .1K
Haloperidol 83 2 8.5 .1K 73 .10K .1K .3K .10K
Iloperidone 129 3.3 7.1 33 0.2 14 3 12.3 .1K
Loxapine 54 10 22 .2K 3.9 21 151 2.8 175
Lumateperone 52 32 NA NA 0.5 173 NA .1K NA
Lurasidone NA 1.7 NA 6.8 2 40.7 .1K .1K
Olanzapine 58 72 49 .2K 3 24 314 4.9 24
Paliperidone 41 9.4 0.5 637.8 1.9 100.3 4.7 5.6 .10K
Perphenazine 28.2 1.4 2.1 421 5.6 132 810.5 8 NA
Pimavanserin NA NA NA NA 0.4 16 NA NA NA
Pimozide 5,495 0.65 0.25 650 19 .3K .1K 692 800
Quetiapine 900 567 940 431 366 .1K .3K 7.5 858
Risperidone 60.6 4.9 9.6 427 0.19 94.9 151 5.2 .10K
Thioridazine 89 10 7.4 108 11 69 134 14 33
Thiothixene 51 1.4 0.4 410 111 .1K 80 12 .10K
Trifluoperazine NA 1.3 NA 950 13 378 653.7 63 NA
Ziprasidone 30 4 7.2 76 2.8 68 160 130 .10K
a
NA5not available.

guide clinical decision-making regarding APDs, as they do in
many other areas of medicine, but are not yet mature enough
to be useful for general clinical practice (10, 11).
While the APDs are the most versatile, and perhaps most
powerful, of the pharmacologic armamentarium available to
treat behavioral disorders, their misuse can lead to signifi-
cant harm. Clozapine has been identified as the most unique
and powerful of this diverse group of drugs, often referred to
as the “gold standard.” However, because it has a greater side
effect burden than any other APD and requires monitoring
for agranulocytosis, it is underused, even for suicide risk
reduction, where it is the only APD approved for this life-
saving indication (12, 13). Clozapine may also have benefit for
this purpose in bipolar disorder (14) and other diagnostic
groups (e.g., PTSD). The risk of using clozapine has been
exaggerated, just as have been some of its benefits (15). In-
sufficient use of clozapine is due, in part, to weakly sup-
ported challenges to its efficacy for suicide prevention (16)
and, in part, because of the side effects of clozapine and
weekly monitoring of the white blood cell count (15).
The failure to appreciate the pharmacologic diversity of
the atypical APDs has hindered the development of superior
APDs that could rely, in part, on some of their differential
pharmacology, e.g., 5-HT7 receptor blockade, release of
cortical glutamate, and indirect and direct 5-HT1A partial
agonism (7, 17). Many clinicians and basic scientists believe
that the atypical APDs are effective only for delusions and
hallucinations. However, as adjunctive agents, they are also
effective for treating aggression, anxiety, mood symptoms,
and obsessive-compulsive symptoms, to name other estab-
lished common uses (18). Most importantly, their ability to
treat cognitive impairment, the most controversial aspect of
their utilization, and to this author their most compelling
advantage, has been challenged despite much preclinical and
clinical evidence that they are effective in this regard in
many patients, enabling dramatic restoration of work and
social function (9).
Subchronic phencyclidine (PCP) treatment followed by
withdrawal in rats has been shown to produce N-methyl-D-
aspartate receptor (NMDAR) hypofunction in cortical slices.
Lurasidone and clozapine have been shown to correct this
defect in a 5-HT7-dependent manner (19). Subchronic PCP
treatment has been shown to dysregulate the balance be-
tween GABA and glutamate in mouse hippocampus, leading to
an increased threshold for inhibition in hippocampal slices
(20). Two drugs which enhance GABAA function in vivo, the
neurosteroid pregnenolone, and the GABAA agonist, TPA-023,
have been shown to restore novel object recognition in mice that
had received subchronic PCP treatment (21, 22). Pregnenolone has
shown some promise in the treatment of cognitive impair-
ment and negative symptoms in schizophrenia (23).
CONTRASTING THE LIMITED VERSUS DIVERSE
PHARMACOLOGY OF THE TYPICAL AND
ATYPICAL APDS
The efficacy of chlorpromazine, the first APD shown to treat
the positive symptoms of schizophrenia, was discovered by

4 focus.psychiatryonline.org Focus Vol. 19, No. 1, Winter 2021


Delay and Deniker in 1952 (24). This discovery transformed
the treatment of this previously intractable illness that af-
fects 1%21.5% of the population worldwide. The subsequent
identification of striatal dopamine D2 receptor blockade
as the basis for its antipsychotic action by Arvid Carlsson
and others led to the development of many antipsychotic
agents—with the same mechanism of action—of diverse
chemical classes. Of these, the most widely used have been
haloperidol, fluphenazine, trifluperazine, perphenazine,
mesoridazine, and thiothixene. Many, especially haloperidol,
are still used for maintenance treatment. Although varying
slightly in affinities for receptors other than dopamine D2
receptors, the evidence that these other actions add signifi-
cantly to their efficacy as antipsychotics is minimal (7). In-
deed, until recently it was widely believed that all APDs act
only through D2 receptor blockade (7, 25). It has been sug-
gested that differences in their rate of dissociation from the D2
receptor was a critical variable in their relative ability to pro-
duce motor side effects (26). However, the evidence for this
hypothesis has not been confirmed (27). Sertindole, olanzapine,
and asenapine are atypical APDs with rates of dissociation from
the D2 receptor that are the same as, or even slower, than that
of haloperidol. Efforts by major pharmaceutical companies to
develop novel atypical APDs on the basis of fast dissociation
from the D2 receptor have been unsuccessful.
Development and application of a rational psychophar-
macology is necessary for optimal choice and use of APDs.
This contrasts with the irrational psychopharmacology that
is widely practiced that takes many forms. These include
trial durations that are too short before switching to another
drug, initiating polypharmacy without an adequate trial
of monotherapy, nonscience-based choice of adjunctive
treatments, dosages that are too low or too high, failure to
address nonadherence to oral or long-acting formulations,
underutilization of long-acting formulations to improve
compliance, and failure to appreciate the differences in
mechanism of action among the ever increasing numbers of
atypical APDs. A rational psychopharmacology must be
based on greater understanding of the domains of psycho-
pathology found in the wide spectrum of clinical diagnoses
for which APDs are used, including bipolar disorder, major
depression, OCD, and aggression. Appreciation of schizo-
phrenia as a syndrome made up of four types of clinical
symptoms—cognitive impairment (which includes disorga-
nized thinking), positive symptoms (delusions and halluci-
nations), negative symptoms (predominantly deficits in
social interaction, experience of reward, and motivation),
and mood symptoms—is essential for a rational psycho-
pharmacology and the development of treatments that are
superior in efficacy and safety. The importance of a multi-
dimensional perspective became evident to me through my
initial clinical experience with using clozapine in treatment-
resistant schizophrenia (28). That experience led to a
greater understanding that the goal of treating schizophre-
nia goes far beyond treating positive symptoms, which un-
fortunately is the clinical standard too often applied (15). The
Focus Vol. 19, No. 1, Winter 2021
MELTZER AND GADALETA
overemphasis on positive symptoms as the goal of drug de-
velopment for APDs and their clinical applications contrib-
uted greatly to the stagnation in the development of superior
treatments of schizophrenia.
THE IMPORTANCE OF TARDIVE DYSKINESIA
The persistent widespread use of typical APDs is due, in part,
to underappreciation of the importance of tardive dyskinesia
(TD) and its importance to the development of cognitive
impairment and its amelioration. Emil Kraepelin (29) and
others reported dyskinesias in patients prior to the discovery
of APDs. My first use of clozapine confirmed its remarkable
ability to improve psychosis and TD in treatment-resistant
schizophrenia and to improve cognition. All aforementioned
domains of psychopathology responded to clozapine in a pa-
tient near death due to TD (30). The ability to improve cog-
nition in this patient was confirmed in a larger group of
patients with and without TD (31). That report helped to
initiate many additional studies with other newly developed
atypical APDs, including risperidone, olanzapine, and que-
tiapine, which were meta-analyzed (32, 33). Preexisting dys-
kinesia and the emergence of TD during treatment with
typical APDs is associated with cognitive impairment (34). As
will be discussed, TD can impair the cognitive improvement
made possible by treatment with atypical APDs (35).
TD can develop rapidly or slowly, depending on genetic vul-
nerability, age, sex, and psychiatric diagnosis. In younger patients,
the annual rate is between 3% and 5%. It is higher in bipolar
disorder than schizophrenia, particularly in patients 60 years old
or older. The average maintenance doses of haloperidol (6–12 mg/
day or its equivalent) are twice the 3–4 mg/day required for
optimal efficacy in most patients (36). Although it may be re-
versible in some patients, TD can be irreversible, extremely se-
vere, and in rare instances life-threatening (37). Its occurrence can
be minimized by using an atypical APD without supplementation
by a typical APD, which enhances D2 receptor blockade.
Recently, inhibitors of the vesicular monoamine transporter
VMAT2, valbenazine and deutetrabenazine, have been shown to
diminish the motor symptoms of TD and have received FDA
approval for this indication (38). VMAT2 is present in the
membrane of secretory vesicles and transports dopamine (DA),
norepinephrine, serotonin, histamine, glutamate, and GABA into
vesicles for presynaptic release (39). An acute dose of NBI-
98782, the active metabolite of valbenazine, given to mice at-
tenuated PCP- and amphetamine-induced hyperlocomotion,
suggesting possible beneficial antipsychotic effect, as well as
effects on cognition and negative symptoms. Acute NBI-98782
also enhanced cortical acetylcholine and GABA efflux and sup-
pressed clozapine-, olanzapine- and risperidone-induced do-
pamine efflux in both the cortex and striatum and cortical
acetylcholine efflux. NBI-98782 also suppressed haloperidol-
induced striatal dopamine efflux (39). These effects may ac-
count for its beneficial effects on TD. Thus, VMAT2 inhibitors
may have clinical utility beyond the control of TD. There is no
published evidence of their effect on cognitive impairment in
focus.psychiatryonline.org 5
CONTRASTING TYPICAL AND ATYPICAL ANTIPSYCHOTICS
patients. Despite the iatrogenic nature and potential gravity of
TD, lack of information and the low cost of typical relative to
that of atypical APDs contributes greatly to the continuing use
of typical APDs.
THE NEUROBIOLOGY OF APDS AS A GUIDE TO
THEIR OPTIMAL USE
The serendipitous discovery of the antipsychotic properties of
chlorpromazine in chronic schizophrenia patients was followed
quickly by the demonstration by Arvid Carlsson and others that
ability to inhibit the action of dopamine at striatal D2 dopamine
receptors was the main basis for its antipsychotic efficacy. The
D2 receptor is highly expressed in the basal ganglia and the
brain stem, less so in the prefrontal cortex and hippocampus,
which is enriched in dopamine D1 receptors (40). These two
types of DA receptors oppose each others’ cellular effects and
must be optimally balanced for normal cognitive function; too
little or too much D1 receptor activity interferes with working
memory and other cognitive measures and other behavioral
domains (41). A placebo-controlled randomized trial demon-
strated that a selective D1 receptor antagonist increased, not
decreased, the severity of psychosis in patients with schizo-
phrenia (42). Atypical APDs, because of their ability to stimulate
the release of dopamine in cortex and other brain regions, may
be thought of as indirect dopamine D1 agonists. Clozapine is also
a D1 agonist and produces equal occupancy of D1 and D2 re-
ceptors in humans, indicating that clozapine may enhance D1
receptor stimulation, both indirectly and directly (43, 44)
A key advance in our understanding of the role of dopamine
in brain function was the identification of the phosphorylation
of DARPP-32 (dopamine- and cyclic-AMP-regulated phos-
phoprotein of molecular weight 32,000) by dopamine and
cyclic AMP in intact nerve cells. DARPP-32 impacts the
concentration of the second messenger, cyclic AMP, via in-
hibition of protein phosphatase-1 (PP1) and through that
mechanism, neuronal signaling (45). This led to the Nobel
Prize for Paul Greengard, which was shared with Carlsson
and Eric Kandel, whose research on the cellular basis of
memory in invertebrates helped to understand the role of
dopamine and other neurotransmitters in the cognitive im-
pairment of schizophrenia (46). The change in PP1 activity
following the release of dopamine can, in turn, alter the
activity of many downstream proteins critical for brain
function. This process is an example of the signaling induced
by all neurotransmitters and neuromodulators required for
an organism to respond to changes in its environment and to
internally generated perturbations that enable harm avoid-
ance, achievement of a desired goal (e.g., reward), experi-
ence less stress, avoidance of cell injury, and death. Signaling
by dopamine is a critical means of inducing synaptic plas-
ticity, which is the basis for learning and memory (46).
Synaptic plasticity refers to changes in synaptic structure
and function that enable learning and memory. This is the
process by which synapses strengthen or weaken over time
6 focus.psychiatryonline.org
in response to increases or decreases in their activity, leading to
learning and memory. Atypical APDs have been shown to have
profound effects on synaptic plasticity (47). For example, acute
and chronic treatments with the atypical antipsychotic lur-
asidone, which has been shown to be effective to improve
psychosis, depression, and cognitive impairment, was shown to
alter the expression of the activity-regulated genes that are
related to these actions (48). This multireceptor targeting agent
shares with most atypical APDs higher affinity for 5-HT2A than
D2 receptors. However, its efficacy as an antipsychotic is also
related to its potent 5-HT7 receptor antagonism and 5-HT1A
partial agonism (49). These two serotonergic effects combined
with weak D2 receptor antagonism are synergistic. There is
conflicting clinical data concerning the relevance of 5-HT3
receptors to the efficacy and side effect of APDs (50), so this
receptor will not be further discussed.
Recent genetic studies with lurasidone indicate that its
effects on synaptic plasticity may be of great importance for
its ability to ameliorate positive and negative symptoms as
well as cognitive impairment (51, 52). The antidepressant
action of amisulpride, a novel atypical antipsychotic that
lacks 5-HT2A antagonism and is not approved in the United
States (although widely used in many other countries to treat
schizophrenia and major depression), was prevented in
5-HT7 receptor knockout mice (53). 5-HT7 receptor antag-
onism is also central to the action of asenapine, clozapine,
and risperidone but not olanzapine or ziprasidone. The
5-HT7 receptor has multiple influences on dopaminergic
function, which enable it to fine tune dopamine function in a
manner not available to typical APDs (54, 55), even though
some typical APDs (pimozide, chlorprothixene, chlorprom-
azine, clothiapine, and fluphenazine) have high affinities for
5-HT7 receptors (56). This is because of their high potency
to block D2 receptors. Thus, the diversity in affinities for
5-HT7 receptors relative to dopamine D2 and 5-HT2A re-
ceptors of the atypical APDs is highly likely to be relevant to
intraindividual differences in clinical effects of atypical
APDs. As noted by Li et al. (52), the expression of 44.5% of
the genes that predicted response to lurasidone were in-
versely related to the expression of 5-HT7 receptors in the
hippocampus and prefrontal cortex of postmortem brain
tissue from schizophrenia patients. These included genes
that are significantly decreased in schizophrenia patients (52).
HIGHLIGHTING DIFFERENCES AMONG
ATYPICAL APDS
There are now many clinical studies that have compared
typical and atypical APDs, providing the basis for many
meta-analyses and reviews. These have generally, but not
always, shown significant advantages for specific domains of
psychopathology, including positive and negative symptoms
and cognition, side effects (particularly extrapyramidal side
effects), and prolactin elevations (with the exception of ris-
peridone, which has a still unexplained ability to produce
prolactin elevations comparable to typical APDs). These
Focus Vol. 19, No. 1, Winter 2021

advantages for efficacy and safety, especially avoidance of TD,
have been found in first-episode schizophrenia (57) as well as
chronic schizophrenia (10) and bipolar disorder (58). They are
not disorder specific or age related. Because of the diversity of
the atypical antipsychotic drugs, weight gain (clozapine,
olanzapine) and prolactin elevations (risperidone) can be
avoided by choice of an atypical with little or no problem in
these regards (e.g., aripiprazole, cariprazine, lurasidone, and
ziprasidone). Nevertheless, because of their low cost, some
have argued for continued use of typical APDs as first-line
treatments, minimizing the lost opportunities for benefits
discussed herein (59, 60). Both typical and atypical APDs are
available as long-acting formulations. The atypicals with long-
acting formulations include aripiprazole, olanzapine, paliper-
idone, and risperidone. Long-acting formulations have distinct
advantages for compliance in both recent-onset schizophrenia
and chronic schizophrenia. They are relatively costly com-
pared with oral atypicals that are now generic but should be
used when compliance with oral medication is erratic (61).
The most influential publication that has contributed to
the continued use of the typical APDs despite the evidence
that the atypical APDs are more effective and safer is the
Clinical Antipsychotic Trials of Intervention Effectiveness
(CATIE) study (62). The current generation of prescribers
may need to be reminded of its history. CATIE was an
18-month randomized controlled trial in nearly 1500 chronic
schizophrenia patients with mild-moderate symptoms de-
spite treatment with typical or atypical APDs. The drugs
studied included aripiprazole, quetiapine, olanzapine, and
risperidone, the first-line atypical APDs available at that
time, along with perphenazine, a representative typical APD.
Perphenazine was chosen to represent the typical APDs
because it was seldom used compared with haloperidol. The
CATIE study was funded by NIMH, and its conclusions
were trumpeted by the authors and NIMH as the first un-
biased comparison of these agents. The results of the study
received vast publicity in popular media worldwide. As of
September 24, 2020, there were 7000 citations in PubMed.
The CATIE study, a noninferiority study, concluded that
there was an absence of evidence for the superiority of
atypical versus typical APDs for nonacute schizophrenia.
Both types of APDs were said to have similar therapeutic
potential and to produce nonsignificantly different out-
comes. It was also concluded that both types of APDs are
similar in mechanism of action, thus explaining their lack of
difference for treating positive symptoms, negative symp-
toms, and cognitive impairment. The CATIE study provided
a minimal examination of the efficacy of clozapine in sub-
jects who completed or dropped out of the main study (63).
Although intended to include only nonresponders to the
drugs in the main study, it allowed patients who did not meet
that criteria to be included, minimizing its value (64).
According to the CATIE lead authors, the CATIE study had
little, and even then short-lived, impact on clinical practice
as use of atypical APDs changed little. This led the CATIE
leadership to reiterate their perspective that the widespread
Focus Vol. 19, No. 1, Winter 2021
MELTZER AND GADALETA
utilization of atypical APDs was the result of pernicious
marketing skills of industry, not valid proof of special benefit,
while always being cautious to put clozapine in a favorable
light (5). They called for better education of physicians about
adhering to the recommendations of the CATIE study to
minimize the use of atypical antipsychotics other than clo-
zapine (65). It is beyond the scope of this article to provide a
full critique of the CATIE study. The self-corrected error with
regard to greater cognitive benefits of the atypical APDs in pa-
tients without TD (35) will be discussed subsequently. Leucht
et al. (1) compared the efficacy and tolerability of 15 typical and
atypical APDs in a meta-analysis involving 212 studies and 47,000
patients. It included a number of findings, including all-cause
discontinuation, the chief outcome measure of the CATIE
study, that favored the atypical APDs over haloperidol,
which clearly had the poorest outcome. The conclusion of
the study was, as noted here, that APDs differed substantially
in side effects and have small but robust differences in global
measures of efficacy. The authors recommended clinicians
focus their choice of APDs for individual patients on the
specific domains identified herein.
HOW THE COMPLEX PHARMACOLOGY OF
ATYPICAL APDS AND THE NEUROBIOLOGY OF
SCHIZOPHRENIA INFORMS OPTIMAL UTILIZATION
OF APDS
It is no longer tenable to conclude that only dopamine D2
receptor blockade contributes to the antipsychotic actions of
typical and atypical APDs. D2 receptor blockade is clearly
the major basis for initiating the antipsychotic action of
typical antipsychotics but downstream effects on other in-
tracellular mechanisms may also contribute. However, D2
receptor blockade is only partially responsible for initiating
the antipsychotic action of the atypical antipsychotics. The
atypical APDs have been aptly described as “magic shot-
guns” (6) because of the large number of different G-protein
receptors whose activity is directly or indirectly affected by
some, but not all, of the atypical APDs. From a receptor
perspective, the antipsychotic effect of the atypical agents is
derived from their more potent 5-HT2A relative to weaker
D2 receptor antagonism, with additional contributions from
direct actions at 5-HT1A, 5-HT6, 5-HT7, histaminergic, and
alpha2 adrenergic receptors (17). The demonstration of the
importance of more potent 5-HT2A than D2 receptor an-
tagonism for distinguishing atypical from typical antipsy-
chotics facilitated the development of risperidone and
olanzapine and most of the other atypical APDs. The com-
bination of these two actions enabled a more rapid onset of
antipsychotic action than strong D2 receptor antagonism
with equivalent or weaker 5-HT2A receptor antagonism (8).
These direct effects of the atypical APDs also contribute
to some of their indirect actions, especially the release of
acetylcholine, glutamate, and dopamine (66, 67), effects which
the typical APDs are not only devoid of, but may even block
when the two classes of drugs are prescribed simultaneously
focus.psychiatryonline.org 7
CONTRASTING TYPICAL AND ATYPICAL ANTIPSYCHOTICS
(68). This type of polypharmacy is common in the treatment
of schizophrenia and bipolar disorder and may lead to lesser
efficacy and more side effects (69, 70). The release of acetyl-
choline by lurasidone, leading to the stimulation of both nic-
otinic and muscarinic receptors in rat cortex, is an essential
component of the ability of lurasidone to restore declarative
memory in rats with memory impaired by prior treatment for
7 days with PCP (71), the most widely studied rodent model of
cognitive impairment in schizophrenia (72, 73). 5-HT2A re-
ceptor blockade, produced by 5-HT2A inverse agonists such
as pimavanserin, have been shown to be critical to the anti-
psychotic action of atypical APDs in the PCP model of
schizophrenia (68, 74). Inverse agonists block the constitutive
activity of receptors. They may also block the activation of the
receptor from endogenous or exogenous neurotransmitters,
as is the case with pimavanserin. This is highly relevant to the
efficacy of pimavanserin, which has been shown to be effec-
tive to treat psychosis in Parkinson’s disease (75). The top-line
unpublished results of a single phase 3 study of pimavanserin
(the ADVANCE trial) reported it to be superior to placebo as
augmentation treatment of persistent negative symptoms in
chronic schizophrenia (see Clinicaltrials.gov NCT02970305
for design of the trial). These results require confirmation.
Pimavanserin has been shown to be useful when combined
with low-dose risperidone—but not low-dose haloperidol—in
acutely psychotic schizophrenia patients (76) but has not been
tested for efficacy as monotherapy. Other selective 5-HT2A
inverse agonists (e.g., SR43469B) have been shown to be ef-
fective as monotherapy in acute schizophrenia (77).
Lumateperone is a 5-HT2A inverse agonist, D2 antagonist,
and 5-HT transporter inhibitor that has recently been shown
to be more effective than placebo in acutely psychotic
schizophrenia patients (78). Unlike the other atypical APDs,
which are more potent 5-HT2A inverse agonists as previously
discussed, it has insignificant binding to other G-protein recep-
tors (e.g., 5-HT1A and 5-HT7 receptors) that contribute to
atypical APDs’ clinical advantages over typical APDs. In ad-
dition to being a postsynaptic D2 receptor antagonist, it is also
a partial agonist at presynaptic striatal D2 receptors, as is
aripiprazole. This presynaptic effect would be expected to
contribute to its ability to increase mesocortical DA release,
and most likely, indirect D1 and D4 agonism (79). Its occu-
pancy of D2 receptors in vivo in human volunteers is com-
parable to that of atypical APDs that lack D2 partial agonism
(80) and is much lower that of aripiprazole. It indirectly
modulates glutamatergic neurotransmission in rats by several
novel mechanisms (79). There are no reported data as to its
ability to affect cognition in rodents or humans or to enhance
acetylcholine release in brain.
Aripiprazole has been reported to improve some do-
mains of cognition in schizophrenia (81). Aripiprazole and
brexpiprazole are atypical APDs that are dopamine D2 re-
ceptor partial agonists with 5-HT1A receptor partial agonist
properties. However, there are significant differences with
regard to receptor pharmacology. Aripiprazole has signifi-
cant 5-HT2A inverse agonism, which brexpiprazole does not.
8 focus.psychiatryonline.org
Nevertheless, both are effective in treating acute schizo-
phrenia with minimal motor side effects and weight gain.
They produce small increases in cortical DA efflux in ro-
dents without increased cortical acetylcholine efflux; the
effect on cortical DA release is related to its 5-HT1A partial
agonism as is its efficacy in restoring declarative memory in
the PCP test (82). Both may benefit from supplementation
with a selective 5-HT2A inverse agonist that has no D2
receptor-blocking properties of note (e.g., pimavanserin).
Cariprazine, another novel atypical APD, also has potent
dopamine D2 and D3 receptor antagonism (but lacks both
5-HT1A partial agonism and 5-HT2A receptor blockade) and
is effective for treating both schizophrenia and mood dis-
orders (83–85). Cariprazine, aripiprazole, and brexpiprazole
may be of particular interest for treating patients who do not
respond adequately to one of the canonical 5-HT2A/D2 an-
tagonists (e.g., risperidone) and prior to a trial of clozapine.
Of these three, cariprazine has the most robust ability to
enhance acetylcholine (86).
The subchronic PCP-induced deficit in cognition in rodents
may result from abnormalities in GABAergic neurotransmis-
sion, which in turn, produce abnormalities in glutamatergic
function, disrupting the synchrony between GABA and gluta-
mate required for effective oscillations and inhibitory and ex-
citatory balance in the brain (20). Stimulation of the release of
acetylcholine by the atypical APDs in cortex, hippocampus, and
other brain regions is one of the major reasons for their ability
to improve cognitive function. Typical APDs do not increase
cortical acetylcholine efflux (66, 67). The loss of cholinergic
stimulation in the aging brain and in neurodegenerative dis-
eases such as Alzheimer’s disease and Lewy Body Dementia is a
major cause of memory impairment in these disorders and can
be at least temporarily and partially remedied by pharmaco-
logic means such as cholinesterase inhibition (87, 88). There is
clinical evidence that release of acetylcholine and stimulation
of muscarinic and nicotinic receptors in cortex and hippocam-
pus by clozapine or the N-desmethylmetabolite of clozapine, or
both, contributes to the improvement in working memory in
both adult and childhood schizophrenia (89, 90). There is also
strong preclinical evidence that supports the efficacy of this
mechanism to improve cognition with other atypical APDs (91).
The direct and indirect actions of the atypical APDs at
G-proteins and chromatin trigger a variety of intracellular
signaling events that lead to modifications of multiple second
messengers, including cyclic AMP, protein modifications and
protein-protein interactions, release of neurotrophins such as
neuregulin and brain-derived neurotrophin (BDNF), and
short- and long-term changes in gene expression (7). Fumagalli
et al (92) demonstrated that the NMDAR uncompetitive
PCP-like NMDAR antagonist MK-801 decreased the BDNF
expression in the hippocampus; olanzapine, an atypical an-
tipsychotic, restored BDNF levels, while haloperidol exac-
erbated the decrease. This study is evidence that BDNF
biosynthesis is differentially modulated by typical and atypical
APDs when NMDA-mediated transmission is reduced, which
is believed to be a key reason for cognitive impairment in
Focus Vol. 19, No. 1, Winter 2021

schizophrenia (93) and the target for the rescue of cognitive
impairment in the subchronic PCP-induced model of cognitive
impairment in schizophrenia (72). Further study is indicated to
determine which atypical APDs can modulate BDNF expression
and, thus, lead to improvement in cognition through enhancing
synaptic plasticity.
Thus, differences in the efficacy of atypical APDs are
related to the underlying neurobiology of the schizophrenia
syndrome and how APDs restore neuronal function. Through
knowledge of these differences and pharmacogenetic guidance,
clinicians will someday be able to choose the best APD and
adjunctive treatments for a patient based on the patient’s ge-
netic and epigenetic endowment, so-called personalized med-
icine. Only some of the knowledge needed for a personalized
approach to prescribing APDs is currently available even with
whole genome scanning and an epigenetic chip analysis of the
epigenome at low cost relative to the cost of the illness. Much
additional research is needed to enable this to be an effective
means of choosing a specific drug, but partial implementa-
tion is possible. An example of this would be measuring the
N-desmethylclozapine/clozapine ratio in plasma and adding
a muscarinic or nicotinic agonist.
Common variants in genes related to synaptic function
have been identified as the best predictors of response to
lurasidone in acutely psychotic patients with schizophrenia
in an association study of GWAS data and changes in total
Positive and Negative Syndrome Scale (PANSS) scores
(DPANSS-T) from the combined data of two 6-week ran-
domized, placebo-controlled trials of lurasidone treatment
in Caucasian schizophrenia patients (51, 52). However, none
reach genome-wide significance. The genomic loci identified
in these hypothesis-free studies include: 1) synaptogenic
adhesion genes (PTPRD, LRRC4C, NRXN1, ILIRAPL1,
SLITRK1, NTRK3); 2) scaffolding proteins (MAGI1, MAGI2,
NBEA), both essential for synaptic function; and 3) other
synapse-associated genes including, NRG1/3, KALRN, and
the neuron-specific splicing regulator RBFOX1. Although
none of these biomarkers reached genome-wide signifi-
cance, most of the genes and associated pathways have been
identified as risk genes for schizophrenia and shown to be
under expressed in postmortem dorsolateral prefrontal
cortex of schizophrenia patients. Some of these genes have
been also shown to predict response to other atypical APDs
(52). These findings add to the evidence that synaptic plas-
ticity is related to multiple aspects of APD response, not just
cognitive impairment, adding to the rationale for favoring
the use of atypical rather than typical APDs.
Awareness of the similarities and differences in phar-
macology of the atypical APDs should increase their
utilization and lead to better outcomes. Rodents treated with
competitive NMDAR antagonists for 3–14 days have demon-
strated that diverse atypical improve some types of cognitive
impairment and social interaction deficits in rodents and
nonhuman primates, while typical APDs do not (72, 73, 94).
The pharmacologic mechanisms that enable the atypical
APDs to restore cognition and social interaction in rodents
Focus Vol. 19, No. 1, Winter 2021
MELTZER AND GADALETA
are diverse and include dopamine D1 and D4 agonism and
5-HT1A partial agonism, as well as restoration of cholinergic
function (71, 91, 94). Ziprasidone, which has 5-HT1A partial
agonist properties and enhances the release of acetylcholine
and dopamine, is among the many atypical APDs with a
similar profile that have been shown to improve cognition
in schizophrenia (95, 96).The extensive evidence for the
role of glutamate, including NMDA receptors in the path-
ophysiology of schizophrenia, have made this model very
attractive for identifying novel treatments for the cognitive
impairment associated with schizophrenia (97). More im-
portantly for the purpose of this article, the studies with the
subchronic PCP are consistent with the findings of multiple
clinical trials (98) that atypical antipsychotics are able to
improve cognition in patients with schizophrenia (9, 32, 95,
96, 99), which was rejected by Keefe et al. (100) based on the
CATIE study. These authors later revised their conclusions
after demonstrating superior efficacy of atypical APDs to
improve cognition in CATIE patients who did not have
overt TD (35). Unfortunately, Caroff et al. (35) did not
call particular attention to this critical issue and it received
little attention subsequently based on the failure to note this
very important caveat when discussing whether or not the
atypical antipsychotics have an advantage over the typical
antipsychotic or how effective they are in treating schizo-
phrenia. The possibility that cognitive impairment in pa-
tients with masked TD (because of maintenance treatment
with antipsychotics) also impairs their ability to respond to
atypical APDs has not been investigated.
When considering the choice of an APD, the risk of TD
must be given high priority because of its impact on potential
improvement in cognition, effect on compliance, and mortality.
This is a major reason for utilizing an atypical rather than a
typical APD for maintenance treatment and even brief treat-
ment, as TD can sometimes develop during the first months of
treatment with typical APDs (37, 101). TD can have a negative
impact on quality of life, with particular impact on social in-
teraction in patients with bipolar disorder, major depression, and
schizophrenia (102). Other types of extrapyramidal symptoms
produced by typical APDs, including increased muscle tone, ri-
gidity, and inaccuracies in fine motor skills can produce negative
subjective responses that lead to noncompliance in patients re-
gardless of diagnosis (103). The risk of TD with atypical APDs is
variable, with clozapine having the lowest risk and risperidone
the highest because of its strong dopamine D2 receptor blockade
(104). Antipsychotic-induced movement disorders should be
assessed at each clinical visit and monitored with rating scales as
needed to facilitate treatment choices (105).
CLARIFYING THE UNIQUE CLINICAL APPLICATIONS
OF CLOZAPINE
As previously noted, clozapine is considered by many to be
an atypical APD in a class of its own, the “gold standard”
with regard to superior efficacy for patients who do not
respond to typical antipsychotics or other first-line atypical
focus.psychiatryonline.org 9
CONTRASTING TYPICAL AND ATYPICAL ANTIPSYCHOTICS
antipsychotics. I have argued here that it is unique for
suicide risk but not for improving cognition. Is it unique
for improving psychosis and overall function in treatment-
resistant schizophrenia? The efficacy of clozapine for
treatment-resistant schizophrenia patients was first estab-
lished in a randomized clinical trial codirected by the author
and others (106). The main conclusion of that study, i.e., that
clozapine is effective in treating positive and negative
symptoms in 30%240% of patients who meet criteria for
treatment-resistant schizophrenia, has been supported by
several decades of experience and numerous other trials
throughout the world in a variety of clinical settings (107).
However, other atypical APDs have also been shown to be
effective in subgroups of patients with treatment-resistant
schizophrenia. This was first reported in a study of mel-
perone (108). Melperone is a member of the same butyro-
phenone chemical class as haloperidol. Melperone was
never developed as an APD in the United States because of a
single paper that claimed that the basis for the efficacy of
clozapine in treatment-resistant schizophrenia was dopa-
mine D4 receptor antagonism (109). The studies supporting
this claim were rejected on a number of grounds and are
inconsistent with the contrary evidence that D4 receptor
stimulation can enhance the ability of clozapine to improve
its efficacy in improving memory in rodents treated with
PCP for 3–14 days (91). The Van Tol et al. (109) report led to a
massive effort by at least four pharmaceutical companies to
be the first to develop selective D4 antagonists, all of which
failed! Indeed, in one study, the selective D4 antagonist
worsened psychopathology in acutely psychotic patients
(110). This is noteworthy since a similar worsening of
schizophrenia occurred in the one clinical trial with a D1
receptor antagonist (42), an indication of the translational
value of rodent studies with regard to schizophrenia. No
further effort to develop melperone for schizophrenia,
which has been shown to be effective to treat psychosis even
in patients with Parkinson’s psychosis (111), occurred in the
United States, a great loss. Subsequently, in randomized con-
trolled trials, olanzapine (112), long-acting injectable risper-
idone (113), lurasidone (114), and aripiprazole (115) were also
found to be effective in treating positive and negative symp-
toms in 30%240% of patients with treatment-resistant
schizophrenia. The overall response rates were similar to that
of clozapine based on historical controls or in the case of
olanzapine, with clozapine as an active comparator. There is
also some evidence that treatment-resistant schizophrenia
with no response to olanzapine or risperidone will improve by
prespecified criteria with aripiprazole (115). Efficacy of various
atypical APDs in patients who fail to respond to typical anti-
psychotics has been widely reported (116).
Based on these studies the argument for early use of
clozapine (i.e., after failure to respond to two APDs, re-
gardless of whether neither or both are atypical [117]), needs
to be reconsidered. Like the suggestion that trials of cloza-
pine in treatment-resistant schizophrenia should be limited
to a few weeks on safety grounds if there is no improvement
10 focus.psychiatryonline.org
after 2 weeks (118), this recommendation to start clozapine is
not supported by the evidence (119). This is also the case for
other atypical APDs. During more prolonged trials, major
changes in synaptic structure and function are quite possi-
ble. Related to this, clinicians should be cautious about em-
bracing suggestions that clozapine should be initiated very
early in the course of the illness without adequate trials of
other atypical APDs that have been shown to be effective in
treatment-resistant schizophrenia (120).
CONCLUSIONS
Atypical APDs have broader efficacy for treating the major
types of psychopathology, including positive, negative, and
mood symptoms and suicidality, compared with typical
APDs. These benefits are evident in a wide range of psy-
chiatric disorders, not just schizophrenia. There is much
greater diversity among the atypical than the typical APDs.
Atypical APDs initiate their actions by targeting multiple
receptors and neurotrophin, leading to synaptic plasticity,
unlike the typical APDs, which selectively act through D2
receptor blockade to mainly target positive symptoms and
produce serious mechanism-based side effects, especially
tardive dyskinesia. 5-HT2A receptor blockade and release
of neurotrophins, such as BDNF, are the most common
mechanisms by which atypical APDs supplement weaker
D2 receptor blockade to achieve their broader action. Di-
rect effects on 5-HT1A and 5-HT7, and indirect effects on
dopamine D1, D4, nicotinic, and muscarinic receptors due
to the release of cortical and hippocampal dopamine and
acetylcholine, are principal contributors to their broader
actions. The benefits from atypical APDs are achieved, in
part, through synaptic plasticity that may take weeks to
months to be achieved. Because of differences among the
atypical APDs and genetic and epigenetic differences
among patients, multiple trials of atypical agents may be
required to find the best drug for a patient until pharma-
cogenetic and other predictors of differential response are
identified. Clozapine, while uniquely effective to reduce
the risk of suicide, is not the only atypical APD useful for
patients who fail to respond to first-line typical and atypical
APDs. Clinicians should be aware of the risk of TD with
typical APDs and its potential to reduce the ability of
atypical APDs to improve cognition. Atypical agents that
target GABA receptors and use of biomarkers, especially
pharmacogenomics markers, will likely expand the ad-
vantages of atypical APDs in the near future.
AUTHOR AND ARTICLE INFORMATION
Departments of Psychiatry and Behavioral Sciences, Pharmacology,
and Physiology, Northwestern University Feinberg School of Medicine,
Chicago. Send correspondence to Dr. Meltzer (h-meltzer@northwestern.
edu).
This work was supported in part by donations from the Price and
Weissman family.
The authors thank Dr. Ronald Salomon for help in preparing the table
and manuscript.
Focus Vol. 19, No. 1, Winter 2021

Dr. Meltzer has received grant support in the past five years from
ACADIA, Allergan, Janssen, Neurocrine, Sepracor, and Sumitomo Dai-
nippon and is a shareholder of ACADIA and LB Pharma. Dr. Gadaleta
reports no financial relationships with commercial interests.
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focus.psychiatryonline.org 13
CLINICAL SYNTHESIS
Tardive Dyskinesia: Spotlight on Current Approaches
to Treatment
Sarah M. Debrey, M.D., and David R. Goldsmith, M.D.
Tardive dyskinesia (TD) is a debilitating, iatrogenic, and potentially
severe movement disorder characterized by involuntary,
repetitive, purposeless movements that are present throughout
the body. The authors present a review of studies of past, current,
and possible future treatment approaches to the management
of TD; consider the phenomenology, assessment, and putative
pathophysiological mechanisms of TD, early pharmacological
trials, a focus on the newer vesicular monoamine transporter
2 inhibitors, and other evidence-based approaches, such as
Tardive dyskinesia (TD) is an iatrogenic, irreversible, and
potentially severe movement disorder characterized by in-
voluntary, repetitive, purposeless movements, typically of
the orofacial muscles but also often affecting muscles of the
trunk, limbs, and head. The term tardive dyskinesia, origi-
nally coined in 1964 by Faurbye et al. (1), refers to the dys-
kinetic movements witnessed among those with long-term
exposure to antipsychotic medications. However, TD can
occur among patients exposed to any dopamine receptor
blocking agent (DRBA), including nonpsychiatric medica-
tions such as metoclopramide. These hyperkinetic move-
ments are often not only burdensome but also lead to
psychological stress and impaired quality of life during a
patient’s recovery efforts (2).
Multiple scales have been developed to assess the severity
of TD, as well as that of other drug-induced movement
disorders. The Extrapyramidal Symptoms Rating Scale is a
seven-item scale that addresses four types of drug-induced
movement disorder: parkinsonism, akathisia, dystonia, and
TD (3). The Simpson Rating Scale is a 15-item scale that
focuses on movements in the orofacial region, neck, trunk,
and extremities (4). The most frequently used scale, in terms
of both research and clinical use, is the Abnormal In-
voluntary Movement Scale (AIMS), which allows providers
to track a patient’s symptoms over time and determine the
appropriate course of action. The AIMS is a 12-item scale;
items 1–7 measure involuntary movements across regions,
scored on a scale ranging from 0 (no dyskinesia) to 4 (severe
dyskinesia), resulting in a maximum score of 28 (5). Items
14 focus.psychiatryonline.org
clozapine; and present preliminary evidence for newer
approaches, such as deep brain stimulation and repetitive
transcranial magnetic stimulation. On the basis of the evidence
presented here, the authors highlight the importance of early
recognition and assessment of TD, as well as how to best
approach management of these often incapacitating
symptoms.
Focus 2021; 19:14–23; doi: 10.1176/appi.focus.20200038
8–10 measure the severity of the involuntary movements, the
level of incapacitation resulting from them, and the patient’s
awareness of these movements, respectively. Items 11–12 are
related to the patient’s mental status. According to the
Schooler-Kane criteria (6), an AIMS score of at least 2 in two
or more body regions or a score of 3 or 4 in at least one region
for a patient with at least three months of cumulative anti-
psychotic exposure defines a probable diagnosis of TD. Per
DSM-5, older adults may develop symptoms after a shorter
period of antipsychotic use.
TD usually appears after long-term (months to years) ex-
posure to DRBAs, but it has in certain cases been shown to
occur after only a brief exposure (7). Second-generation an-
tipsychotics (SGAs) are historically considered a lower risk
for the development of TD, with a reported cumulative annual
incidence of 0.8%23.0% compared with 5.4%27.7% for first-
generation antipsychotics (FGAs) (8, 9). A 2017 meta-analysis
(10) of 41 studies and 11,493 patients exposed to antipsychotics
found a pooled TD prevalence of 25.3%, with a lower fre-
quency among those with current SGA treatment (20.7%)
than with FGA treatment (30.0%). Patients currently pre-
scribed an SGA with no lifetime history of FGA treatment had
the lowest prevalence of TD at 7.2%. In addition to antipsy-
chotic medication exposure (dose, duration, or type), older
age is another well-established risk factor. Elderly patients
(defined as those with a mean age of 65 years) have a five to six
times greater risk of developing TD (11). Other risk factors
include African American ethnicity, female sex, history of
alcohol or other substance abuse disorders, HIV-positive
Focus Vol. 19, No. 1, Winter 2021

status, diabetes, and use of lithium or antiparkinsonian agents,
in particular anticholinergic medications (12).
The pathophysiology of TD is not fully elucidated, and it is
postulated to have a multifactorial etiology. Several mecha-
nisms have been proposed, with the prevailing hypothesis
implicating postsynaptic dopamine receptor upregulation
following chronic blockade of dopamine receptors in the ni-
grostriatal pathway. This, in turn, may lead to permanent
receptor hypersensitivity and increased affinity for dopamine,
resulting in the characteristic hyperkinetic movements (13).
This model would explain the “masking” of TD that tempo-
rarily occurs with greater dopamine blockade through an
increase in the dosage of the DRBA.
However, this mechanism alone does not account for the
variability in development of TD. Given that all antipsy-
chotic medications are DRBAs to some extent, and yet ap-
proximately one in four patients taking these medications
develops TD, this suggests that other factors, genetic vul-
nerability, or both are also involved. Oxidative stress—
through brain injury, aging, or even neuroleptic exposure
(14)—has been implicated in the development of TD. DRBAs
induce a secondary increase in the synthesis and metabolism
of dopamine (15), and this increased metabolism is associ-
ated with increased free radical production via monoamine
oxidase. Particular antipsychotics, including haloperidol,
have been shown to be directly harmful through the pro-
duction of free radicals. One in vitro study showed that
haloperidol caused apoptotic cell death when administered
to cell cultures of murine neurons, an effect that was at-
tenuated by antioxidants such as vitamin E (16).
Damage to striatal gamma-aminobutyric acid (GABA)-
containing neurons may also contribute to pathogenesis of
TD. In studies of animals after chronic exposure to anti-
psychotic medication, decreased activity of glutamic acid
decarboxylase in the substantia nigra, globus pallidus, and
subthalamic nucleus has been reported (17). However, GABA
agonist treatments in humans have not had robust effects,
with two recent Cochrane reviews finding inconclusive
evidence to support the use of either benzodiazepine or
nonbenzodiazepine GABA agonists in the treatment of
antipsychotic-induced TD (18, 19).
This article highlights the varying treatment options for
TD with a specific focus on the newer vesicular monoamine
transporter 2 (VMAT2) inhibitors. We also provide some
historical context for older approaches to TD treatment as
well as for medications such as clozapine that continue to be
effective yet underused for TD. Last, we review a growing
literature on novel neurostimulation techniques that appear
to offer some potential benefit for more refractory TD cases.
INTERVENTIONS
Ideally, TD would be preventable, although among patients
with a primary psychotic disorder, the long-term use of
DRBAs is typically necessary. However, SGAs are now fre-
quently used with patients with numerous other diagnoses,
Focus Vol. 19, No. 1, Winter 2021
DEBREY AND GOLDSMITH
including bipolar disorder, autism spectrum disorder, and
major depressive disorder, expanding the population at risk
for development of TD. Therefore, it is essential that this
potential risk be thoroughly discussed and that antipsychotic
medications only be prescribed when clinically necessary.
Close monitoring for development of symptoms is also key.
Once TD symptoms are observable, cessation of the
medication may not lead to resolution. In fact, this is one
method of differentiating between TD and parkinsonism.
Although parkinsonism is typically improved by either
complete cessation or decreasing the dosage of the offending
agent, the same is not true for TD. In addition, anticholin-
ergic agents frequently used to treat parkinsonism are con-
sidered ineffective for TD and potentially deleterious (20).
In studies examining the natural history of TD, remission
rates have been highly variable, largely because of hetero-
geneity in rates of continued antipsychotic exposure, sup-
porting the ability of these medications to mask ongoing TD.
Although an older study found remission of TD in 37% of
patients after cessation of antipsychotic medication (21), this
finding has not been replicated. In a retrospective study of
patients with TD resulting from DRBA use for nonpsychotic
conditions (N5108), 13% experienced symptom resolution,
although only 2% achieved this without the addition of
various therapeutic agents (22).
Although it has been postulated that switching from an
FGA to an SGA may lead to improvement in TD, the
American Academy of Neurology has reported insufficient
evidence for switching (23). This was supported by a natu-
ralistic study of 223 patients with severe mental illness and
TD (mean baseline AIMS score 9.1) for whom switching
from an FGA to an SGA or from a high D2 affinity antipsy-
chotic to one with lower affinity had no significant impact on
AIMS score (24). Adding an SGA to an existing FGA resulted
in a 2- to 3-point reduction, and switching to an FGA led to a
three-point reduction, consistent with the masking theory.
Early Medication Trials
No medication carried Food and Drug Administration (FDA)
approval for treatment of TD before 2017, although multiple
agents have been tried off-label. In 2013, the American
Academy of Neurology published treatment guidelines for
TD (23). At that time, results indicated limited evidence for
any treatment, listing only two drugs with level B evidence
(clonazepam and Gingko biloba) and two with level C evi-
dence (tetrabenazine and amantadine).
Given the hypothesis that striatonigral GABAergic path-
ways reduce dopaminergic activity in the substantia nigra via
negative feedback, various GABA agonists have also been
trialed for the treatment of TD. In a small (N519) double-
blind, randomized crossover trial assessing the effect of clo-
nazepam versus placebo, clonazepam treatment decreased
dyskinesia scores by 37.1% versus placebo, an effect that was
quickly reversed with placebo administration (25). Of note,
clonazepam was more effective among patients with dystonic
symptoms than among those with choreoathetoid symptoms.
focus.psychiatryonline.org 15
CURRENT APPROACHES TO TREATMENT OF TARDIVE DYSKINESIA
Amantadine, a noncompetitive N-methyl-D-aspartate re-
ceptor antagonist and dopamine releaser, has also been used
to treat drug-induced dyskinesias, including TD, although
results have been varied and, even in positive trials, of de-
batable clinical significance. An 18-week double-blind cross-
over study of 16 patients with a baseline mean AIMS score of
8.375 randomized to placebo or amantadine administration
(up to 300 mg/day) reported a slight improvement in follow-
up AIMS scores for the amantadine group over the placebo
group (7.312 versus 8.188, respectively) (26). In this trial, pa-
tients were continued on their existing antipsychotic regi-
men, although anticholinergic medications were held. In a
double-blind randomized controlled trial (RCT) comparing
amantadine and placebo among patients with antipsychotic-
induced TD (N522), results demonstrated slight improve-
ment in the average AIMS total score for those randomized to
amantadine (21.8% versus 0% in the placebo arm) at 2 weeks
(27). In an older double-blind crossover RCT comparing
amantadine and biperiden (an older anticholinergic medica-
tion), a similar, though modest, improvement in TD was re-
portedly found for both amantadine and biperiden, but the
full text of this article was not available (28).
In the early 1980s, propranolol was reported to be effective
for the treatment of TD, primarily in case series (29, 30). Pro-
pranolol, a beta-adrenergic receptor antagonist, has anti-
dyskinetic properties postulated to be the result of its
modulation of dopaminergic activity through presynaptic at-
tenuation of dopamine efflux (31). However, when thioridazine
serum levels were reported to be increased by the addition of
propranolol, the question was then whether propranolol was
simply masking TD through the same mechanism as an in-
crease in the antipsychotic dosage (32). Although no additional
trials have investigated the role of propranolol in TD treatment,
a 2012 case series reported improvement in AIMS scores for
two patients prescribed low-dose propranolol for TD after the
offending agents (metoclopramide and risperidone) had been
discontinued, suggesting that propranolol may be efficacious
on its own in treating TD (33).
VMAT2 Inhibitors
Recent studies have focused on the efficacy of reversible
VMAT2 inhibitors in the treatment of TD. VMAT2 is a ve-
sicular protein that transports monoamines, including do-
pamine, noradrenaline, and serotonin from the cytosol into
the membrane, where they are sequestered into vesicles
before release into the synaptic cleft. VMAT2 inhibitors
block this monoamine transport into vesicles, leading to
their degradation in the cytosol (34). This reduction in do-
pamine release in particular, leading to less activation of
postsynaptic dopamine receptors in the nigrostriatal path-
way, is believed to decrease dyskinetic movements. The
VMAT2 inhibitors discussed here are reversible, in contrast
to reserpine, which is an irreversible, nonselective VMAT
inhibitor at both VMAT1 and VMAT2. The pharmacokinetic
and pharmacodynamic profiles of each of the three VMAT2
inhibitors—tetrabenazine (TBZ), deutetrabenazine (DBZ),
16 focus.psychiatryonline.org
and valbenazine (VBZ)—and evidence for their use in
treatment of TD are summarized in Table 1. Of note, all three
VMAT2 inhibitors are metabolized by cytochrome P450
2D6 (CYP2D6) and have the potential to cause Qtc pro-
longation, particularly in poor metabolizers (35).
Tetrabenazine. TBZ, a VMAT2 inhibitor that was FDA ap-
proved for Huntington’s disease in 2008, has long been used
off-label in the treatment of TD. The first randomized trial for
TBZ in treating TD was published in 1972 and demonstrated
significant improvement in frequency of abnormal move-
ments, with resolution of TD in 33% of the 24 enrolled patients
(36). An open-label trial (N520) published in 1999 reported a
54% improvement in AIMS scores (37). However, there are
several limitations to the use of TBZ. Due to its short serum
half-life, tetrabenazine requires three times daily dosing. The
associated high peak concentrations and fluctuations in
plasma levels are believed to be responsible for its poor tol-
erability, including reports of somnolence and depression.
TBZ also carries an FDA black box warning for suicidality in
patients with Huntington’s disease.
Deutetrabenazine. Since the advent of TBZ, two newer
VMAT2 inhibitors have been developed to enhance tolera-
bility via pharmacokinetic and pharmacodynamic improve-
ments. DBZ and VBZ were both FDA-approved for the
treatment of TD in 2017. DBZ is a highly selective VMAT2
inhibitor containing deuterium. The addition of deuterium
slows the metabolism of DBZ, leading to reduced serum-level
fluctuations compared with TBZ, thereby decreasing the
potential for adverse effects associated with peak concentra-
tions. This longer half-life also enables twice daily dosing.
There have been two randomized, double-blind, placebo-
controlled trials of DBZ with published results (38–40)
(summarized in Table 2). Both included 12 weeks of follow-up.
In the Aim to Reduce Movements in Tardive Dyskinesia
(ARM-TD ) study, (38), patients (N5117) were randomized to
placebo versus escalating doses of DBZ, titrated until symp-
toms were adequately controlled or an adverse event occurred,
to a maximum dose of 48 mg/day. A 6-week maintenance
period at the final dosage followed. Although AIMS scores
were significantly reduced in the treatment group, results
were modest (23.0 versus 21.6, p50.019). Similarly, the sec-
ondary outcome of Clinical Global Impression (CGI) score was
rated as “much improved” or “very much improved” for 48.2%
of the DBZ group versus 40.4% for the placebo group. There
were low rates of adverse events in the DBZ and placebo
groups, including depression (1.7% versus 1.7%) and suicidal
ideation (0% versus 1.7%). In addition, no worsening of par-
kinsonism or akathisia was observed in either group.
Similar positive results were also found in the Addressing
Involuntary Movements in Tardive Dyskinesia (AIM-TD)
trial (39). After 8 weeks of maintenance following a 4-week
titration to a lower target dose (12, 24, or 36 mg/day), the
change in least-squares mean AIMS score was significantly
improved in the two higher dosage DBZ groups, with a
Focus Vol. 19, No. 1, Winter 2021

TABLE 1. Comparison of VMAT2 inhibitorsa
Time to peak
Half- concentration,
Affinity for VMAT– life Cmax
Drug 2 (Ki) (hours) (hours)
Tetrabenazine 100 5–7 1–1.5
Deutetrabenazine Multiple metabolites; 9–10 3–4
range, 4.2–690
Valbenazine 150 15–22 4–8
a
VMAT2, vesicular monoamine transporter 2; Cmax, maximum concentration recorded; CYP2D6, cytochrome P450 2D6; CYP3A4, cytochrome P450 3A4.
treatment difference of 21.9 points (p50.001) in the 36 mg/
day group and of 21.8 (p50.003) in the 24 mg/day group,
compared with placebo. The 12 mg/day group did not reach
a statistically significant treatment difference (20.7 points,
p50.217). The proportion of patients who experienced at
least a 50% improvement from their baseline AIMS score
was greater in the two higher dosage groups (24 mg/day:
35%, p50.005; 36 mg/day: 33%, p50.007) compared with
placebo (12%), but this was not true for the 12 mg/day group
(13%). Treatment success defined as “much improved” or
“very much improved” on the CGI was also significantly
higher in the 24 mg/day and 36 mg/day groups (49% and
44%, respectively) versus placebo (26%). The rate of adverse
events was similar in all treatment and placebo groups, with
high mean adherence to the study drug (98%). Two deaths
from cardiac events were reported in the DBZ groups, but
these were not deemed to be related to study drug exposure.
Participants who completed either AIM-TD or ARM-TD
were eligible to enter an open-label extension trial of a 6-week
dose-escalation phase followed by a long-term maintenance
phase of up to 106 weeks (40) in order to evaluate the tolera-
bility and long-term efficacy of DBZ maintenance treatment. Of
the 368 patients who successfully completed the phase 3 trials,
343 patients rolled over into this open-label extension study
(DBZ, N5232; placebo, N5111). After a 1-week washout period
from the phase 3 study drug, DBZ was titrated in a similar
fashion as in the AIM-TD trial, to a maximum of 48 mg/day
(36 mg/day if on concurrent strong CYP2D6 inhibitors), with
more robust improvement reported. The mean change in AIMS
score was 24.9 points at week 54 (N5146) and 26.3 points at
week 80 (N566). The most common neuropsychiatric adverse
events reported included headache, somnolence, depression,
and anxiety, with rates that were comparable to or lower than
those reported in the shorter-term ARM-TD and AIM-TD
phase 3 trials. This study therefore supported the long-term
safety and efficacy of DBZ treatment. Although DBZ carries a
black box warning for suicidality among patients with Hun-
tington’s disease, the data have not showed an increased risk for
suicidality during its use for TD treatment, and therefore DBZ
does not have a regulatory warning for this population.
Valbenazine. VBZ is a highly selective, reversible VMAT2 in-
hibitor with metabolites that have affinity strictly for VMAT2
receptors, thereby minimizing adverse effects. A prodrug of
Focus Vol. 19, No. 1, Winter 2021
DEBREY AND GOLDSMITH
Dosage
range Dosing Need to take
(mg/day) frequency with food? Metabolism
12.5–150 3 times No Hepatic; CYP2D6
daily
12–48 2 times Yes Hepatic; CYP2D6
daily
40–80 Once No (although high-fat Hepatic; CYP3A4,
daily meals lower Cmax) CYP2D6
DBZ, its activation is via hydrolysis and therefore not de-
pendent on hepatic metabolism. Multiple double-blinded,
placebo-controlled trials have demonstrated significant im-
provement in TD among patients randomized to VBZ versus
placebo. Although three studies have shown acute improve-
ment in trials carried out for between six and 12 weeks, others
have been conducted for up to a maximum of 52 weeks to
analyze long-term effects.
The KINECT series of trials (41–45), summarized in Table
3, has provided the majority of the evidence. In the initial
6-week KINECT trial, neither AIMS nor Clinical Global Im-
pression of Change–Tardive Dyskinesia (CGI-TD ) scores
improved with VBZ over placebo (41). In the larger KINECT2
trial, participants were randomized to either placebo or
VBZ, titrated to a maximum dosage of 75 mg/day, depending
on tolerability and response (42). After 6 weeks of follow-up,
there was a mean 3.6-point decrease in AIMS severity score
for VBZ compared with a 1.1-point decrease in that score
for placebo (p,0.001). A significantly greater percentage of
responders (.50% reduction in AIMS from baseline) was
present in the VBZ group versus the placebo group (48.9%
versus 18.2%, p,0.001).
Similar results were found in KINECT 3, both for short-term
(43) and long-term (44) trials. In the 6-week trial, participants
were equally randomized to placebo, VBZ 40 mg/day, or VBZ
80 mg/day. The difference in the least-squares mean change
between baseline and week 6 was 23.2 points in the VBZ 80
mg/day group, 21.9 points in the 40 mg/day group, and 20.1 in
the placebo group, equating to a number needed to treat
(NNT)of 3.2 (rounded up to 4) for the 80 mg/day VBZ group.
The KINECT3 extension study (44) had a 42-week VBZ
extension period, followed by a 4-week washout period, for a
total of 52 weeks of follow-up. Those receiving placebo ear-
lier in the study were randomized to 40 mg/day or 80 mg/day,
and those receiving 40 or 80 mg VBZ were continued on these
doses. During follow-up, AIMS and CGI-TD score improve-
ments were maintained, indicating sustained improvement in
TD. At week 48, mean changes in AIMS scores were 24.8
(80 mg/day group) and 23.0 (40 mg/day group) (p,0.001).
As expected, these improvements were reversible, with scores
returning toward baseline after VBZ discontinuation.
KINECT 4 (45) further evaluated the long-term effects of
VBZ over 48 weeks of follow-up. In this open-label trial
(N5167), treatment was initiated at 40 mg/day and increased
focus.psychiatryonline.org 17
CURRENT APPROACHES TO TREATMENT OF TARDIVE DYSKINESIA

TABLE 2. Efficacy and safety analysis data for DBZa

Study Study design Population Exposure Primary endpoint Efficacy results Adverse events
ARM-TD trial (38) 12-week, TD diagnosis DBZ started at Change in AIMS DBZ reduced least- Low rates of anxiety
N5117 (70% with randomized, for .3 months 12 mg/day (6 mg score from squares mean in DBZ vs. PBO
schizophrenia or double-blind, and history of BID) and titrated baseline to week AIMS scores from groups (3.4% vs.
SCAD), mean parallel-group DRBA weekly by 6 mg/ 12 baseline to week 6.8%), depressed
baseline AIMS study at 46 sites use .3 months day, if required, 12 vs. PBO (–3.0 mood (1.7% vs.
score59.6 in the United (.1 month if for up to 6 weeks vs.–1.6, p50.019). 1.7%), and suicidal
States and age .60). Total until adequate Improvement in ideation (0% vs.
Europe. AIMS motor dyskinesia control AIMS score 1.7%,
Randomized 1:1 score .6. was achieved, a significantly respectively).
for DBZ versus significant AE differed between
PBO. Stratified by occurred, or the the DBZ and PBO
use of DRBA at maximal groups by week 4.
baseline. allowable dose
(48 mg/day) was
reached; this was
followed by
maintenance
(6 weeks) and a
1-week washout.
AIM-TD trial (39) 12-week TD diagnosis DBZ at a dosage of Change in AIMS Change in least- No increased risk of
N5298 (60% with randomized, for .3 months 36, 24, or 12 mg/ score from mean squares akathisia or
schizophrenia or double-blind and history of day. Target dose baseline to week AIMS score parkinsonism was
SCAD), mean study, patients DRBA maintained for 12 improved by –3.3 found in the DBZ
baseline AIMS randomized in a use .3 months 8 weeks. in the DBZ groups vs. the
score ranged 1:1:1:1 pattern to (.1 month if 36 mg/day group, PBO group. Rates
from 9.4 to 10.1 receive 1 of age .60). Total –3.2 in the of depression,
(reported per 3 fixed-dose AIMS motor 24 mg/day group, suicidal ideation,
treatment arm) regimens of DBZ score .6. and –2.1 in the and anxiety were
(12, 24, or 36 mg/ 12 mg/day group, not significantly
day) or PBO. versus –1.4 in the different among
PBO group. This DBZ treatment
equated to a groups vs. PBO
significant group.
treatment
difference of –1.9
(p50.001), –1.8
(p50.003), and
–0.7 (p50.217)
for the 3 groups
respectively,
compared with
PBO.
AIM-TD/ARM-TD Open-label dose- Participants who DBZ at a dosage of Safety assessment, Mean change in Exposure-adjusted
extension trial extension trial had successfully 36, 24, or 12 mg/ plus change in AIMS score was incidence rates of
(40) N5343, (6 weeks) completed day AIMS score from –4.9 at week adverse events
mean baseline followed by AIM-TD or ARM- baseline to each 54 (N5146) and (most common
AIMS score58.8 maintenance TD follow-up visit –6.3 at week including
follow up phase 80 (N566). depression,
(#106 weeks) anxiety, and
somnolence)
were comparable
to that of the
short-term
ARM-TD trial,
indicating no
evidence of
cumulative
toxicity or
tolerability
findings
associated with
long-term DBZ
treatment
a
DBZ, deutetrabenazine; ARM-TD, Aim to Reduce Movements in Tardive Dyskinesia study; TD, tardive dyskinesia; SCAD, schizoaffective disorder; AIMS,
Abnormal Involuntary Movement Scale; PBO, placebo; DRBA, dopamine receptor blocking agent; AIM-TD, Addressing Involuntary Movements in Tardive
Dyskinesia study; BID, twice a day; AE, adverse event.

18 focus.psychiatryonline.org Focus Vol. 19, No. 1, Winter 2021

 DEBREY AND GOLDSMITH

TABLE 3. Efficacy and safety analysis data for VBZa

Primary
Study Study design Population Exposure endpoint Efficacy results Adverse events
KINECT 2 (42) 6-week Moderate to NBI–98854 (VBZ) Change in AIMS AIMS score Most common
N5100 (58% randomized, severe TD at a starting score from improved by adverse events
with double-blind diagnosis at dosage of baseline to –3.6 in the VBZ in VBZ vs. PBO
schizophrenia study of VBZ vs. study entry 25 mg once week 6 group vs. –1.1 group were
or SCAD), mean PBO (assessed via daily, increased points in PBO fatigue (9.8% vs.
baseline AIMS video by by 25 mg every group. A 4.1%), headache
score58.0 movement 2 weeks until significantly (9.8% vs. 4.1%),
disorder reaching greater constipation
specialists) maximum percentage of (3.9% vs. 6.1%)
among patients dosage of responders and urinary tract
with psychiatric 75 mg/day (.50% infection (3.9%
stability reduction in vs. 6.1%),
(BPRS,50) and AIMS from respectively.
history of DRBA baseline)
use present in VBZ
vs. PBO group
(48.9% vs. 18.2%,
p,0.001)
KINECT 3 (43) 6-week double- Moderate to VBZ at 40 mg/day Change in AIMS Mean least- Most common
N5227 (65% blind study, severe TD or 80 mg/day score from squares AIMS adverse events
with randomized 1:1: diagnosis at baseline to score improved VBZ 40 mg/day
schizophrenia 1 to PBO, VBZ study entry week 6 by –3.2 in the group vs. VBZ
or SCAD), mean 80 mg/day, or (assessed via VBZ 80 mg/day 80 mg/day
baseline AIMS VBZ 40 mg/day video by group, –1.9 in group vs. PBO
score510.0 movement the 40 mg/day group were
disorder group, and –0.1 somnolence
specialists), in PBO group. (5.6%, 5.1%, and
history of DRBA NNT54 for the 3.9%), akathisia
use .3 months VBZ 80 mg/day (4.2%, 2.5%, and
group. 1.3%), and dry
mouth (6.9%,
0%, and 1.3%),
respectively.
KINECT 3 42- 42-week VBZ Same as KINECT Participants Change in AIMS AIMS Most common
week extension extension trial 3 initial study randomized score from improvement adverse events
trial (44) N5198, of KINECT3 to PBO in baseline to sustained in 80 mg/day
mean baseline participants 6-week trial week 48 throughout the group vs.
AIMS score59.6 rerandomized 1: extension 40 mg/day
for 40 mg/day 1 to VBZ 40 or period. At week group were
group vs. 10.4 80 mg. Those 48, mean headache (6.9%
for 80 mg/day on VBZ in initial changes in AIMS vs. 7.2%), urinary
group study continued score of –4.8 tract infection
at current dose. for the 80 mg/ (6.9% vs. 7.2%),
day group and diarrhea (7.9%
–3.0 for the vs. 3.1%), and
40 mg/day dizziness (6.9%
group. Mean vs. 4.1%).
percentage of Syncope
improvement occurred in
from baseline 3 patients.
was 30.4% There was no
(80 mg/day worsening of
group) and akathisia or
23.7% (40 mg/ parkinsonism.
day group). AIMS
scores
worsened from
weeks 48–52
after VBZ
discontinuation,
with evidence of
TD returning
toward baseline
levels.
continued

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CURRENT APPROACHES TO TREATMENT OF TARDIVE DYSKINESIA

TABLE 3, continued
Primary
Study Study design Population Exposure endpoint Efficacy results Adverse events
KINECT 4 (45) 48-week open- Moderate to Participants Long-term safety TD improvement The most
N5167 label treatment severe started on VBZ assessment, was sustained common TEAEs
(73% with period followed neuroleptic- 40 mg/day, plus change in throughout ($5% after week
schizophrenia by a 4-week induced TD then changed to AIMS score treatment, with 4) were urinary
or SCAD), mean washout for .3 months 80 mg/day after from baseline to AIMS mean total tract infection
baseline AIMS at study entry, 4 weeks on the endpoint score changes (8.5%) and
score510.0 stable basis of efficacy from baseline to headache
psychiatric and tolerability week 48 of (5.2%).
status, medical –10.2 (40 mg/
stability day group) and
–11.0 (80 mg/
day group). AIMS
scores trended
back toward
baseline during
washout period.
a
VBZ, valbenazine; SCAD, schizoaffective disorder; AIMS, Abnormal Involuntary Movement Scale; PBO, placebo; BPRS, Brief Psychiatric Rating Scale; DRBA,
dopamine receptor blocking agent; NNT, number needed to treat TEAE, treatment-emergent adverse event.

to 80 mg/day at week 4 on the basis of individual tolerability
and response, in order to simulate real-world clinical situations.
Mean AIMS score improvement for the 40 mg/day group was
10.2 points, compared with 11.0 points for the 80 mg/day group.
Among all participants, treatment response (.50% improve-
ment on AIMS) was found to be 90%. During the extension
period, 69.2% of patients reported at least one adverse event,
with headache being the most common (7.2% versus 6.9% for
the 40 mg/day versus 80 mg/day groups, respectively). Dis-
continuation rate due to any adverse event was 15.7%.
Serious adverse events were observed among 14.6%, al-
though the only serious event occurring for more than two
participants was syncope (N53). VBZ treatment did not induce
or worsen parkinsonism or akathisia, as measured by the
Simpson-Angus Scale and the Barnes Akathisia Rating Scale.
No clinically meaningful changes were reported in vital signs or
electrocardiogram parameters during the extension trial. Sui-
cidal ideation was reported among 5.1% of participants, and
suicidal ideation or behaviors led to treatment discontinuation
by five people, although these were judged by site investigators
to be unlikely to be related to VBZ. It is noted that few par-
ticipants had worsening of scores on the Columbia Suicide
Severity Rating Scale for suicidal ideation, despite nearly a third
having a lifetime history of suicidality. This study further sup-
ported the long-term safety and efficacy of VBZ, even among
older patients. When patients were dichotomized at age 55, no
significant differences were found between older and younger
groups in regard to either efficacy or adverse events.
Clozapine
Clozapine is an SGA and the only FDA-approved antipsy-
chotic medication for treatment-resistant schizophrenia.
Although there have been reports of clozapine worsening or
inducing TD (46), the majority of evidence supports its use
as an effective treatment for TD. An early 2001 meta-analysis
evaluated the effectiveness of SGAs among patients with
treatment-resistant schizophrenia on outcomes related to
symptoms as well as side effects, including TD (47). The
meta-analysis found a significant decrease in TD among
patients treated with clozapine, although the effect was
nonsignificant when compared with other SGAs.
Since that initial study, a more recent meta-analysis investi-
gating the effect of switching from a nonclozapine antipsychotic
to clozapine for TD demonstrated that in studies of patients with
schizophrenia, switching to clozapine resulted in a significant
reduction in symptoms of TD (effect size of 0.4, indicating a
small to moderate effect) (48). Although there was significant
heterogeneity in the studies included in the meta-analysis in
regard to baseline severity of TD, the meta-analysis demon-
strated the most significant reductions in those studies of indi-
viduals (N54 studies, 48 patients) with moderate to severe TD.
These findings were further supported by a larger recent
systematic review demonstrating effectiveness for switching
from either FGAs or SGAs to clozapine across 13 studies (46).
The review also demonstrated a negative association between
duration of clozapine use and severity of TD symptoms, with
variability among studies regarding time to significant re-
duction in symptoms that ranged from four to 12 weeks.
Moreover, longer trials have supported a sustained effect over
time (49–51). This review also found a significant negative
relationship between TD severity and mean clozapine dose,
which suggests that improvements in TD symptoms may be
found early in the course of clozapine titration even before
achieving a meaningful antipsychotic effect.
One possible explanation for the role of clozapine in the
treatment of TD may be supported by the hypothesized mech-
anisms of TD. Postsynaptic D2 receptor upregulation or potential
hypersensitivity of these receptors may be mitigated by the low
affinity of clozapine for the dopamine D2 receptor as opposed to
other antipsychotics that have greater affinity for that receptor
(52, 53). Moreover, because of its quick dissociation from the
D2 receptor, it is unlikely that the effect of clozapine on TD
symptoms is due to a masking effect but is rather likely due to
other mechanisms that warrant further investigation.

20 focus.psychiatryonline.org Focus Vol. 19, No. 1, Winter 2021


Neurostimulation
In severe, refractory cases of TD, neurostimulation via deep
brain stimulation (DBS) or repetitive transcranial magnetic
stimulation (rTMS) has been studied. A recent meta-analysis
described cases of 117 patients who underwent elective DBS
(for the majority, the bilateral posteroventral globus pallidus
pars interna was targeted) to treat refractory tardive syn-
dromes (54). Whereas most cases were open label, four
studies (N531) reported on assessments that were done in a
double-blind fashion (55–58). Of note, the majority of cases
(N5113) were patients with tardive dystonia. All but two cases
in this analysis were patients treated with antipsychotic
medications. Patients showed significant improvement on the
AIMS (mean6SD 62615%) and the Burke-Fahn-Marsden
scale (76621%) after DBS. Although the included data were
heterogeneous in terms of recruitment, severity, assessment,
and so forth, the data from these case studies suggest that DBS
may be an effective option for severe treatment-refractory
cases with significant disruption in quality of life.
One RCT of pallidal DBS versus sham treatment has been
conducted with patients with tardive syndromes (dystonia
and dyskinesia) (59). Although patients in the active DBS
condition showed a 22.8% improvement in their symptoms at
3 months, this was not statistically significantly different from
the sham group, who showed a 12.0% improvement. Patients
went through an open-label extension phase for 6 months and
demonstrated an overall improvement of 41.5%. Adverse
events occurred in 10 of 25 cases and included DBS lead
discomfort, gait disorders, dysarthria, confusion, skin erosion
(DBS lead), pulmonary embolism, and in one case aggravation
of dyskinesia as a result of a gastrointestinal infection. All
adverse events resolved, suggesting that DBS for tardive
syndromes may be a safe option. Further RCTs will be im-
portant to provide evidence that DBS is an effective treatment
option for patients with severe TD.
Given these DBS findings, Khedr et al. (60) suggested that
tardive syndromes may result from a distributed cortico-
striatal network that may be modulated by rTMS. The au-
thors conducted a double-blind RCT of rTMS versus sham
over the motor cortex with 26 patients for 10 consecutive
days. The active rTMS group showed a significantly greater
reduction in AIMS scores (8.361.7 points), as tardive
symptoms compared with the sham group (1.263.3). It is
important to interpret this finding with caution, given that it
represents one single-site study whose findings will need to
be replicated in multiple larger trials across sites. If repli-
cated, rTMS may be an effective option for medication-
refractory patients who do not want to progress to DBS.
Miscellaneous Treatments
Agents often used in the treatment of Alzheimer’s disease that
have cholinergic properties (e.g., cholinesterase inhibitors),
such as galantamine, donepezil, and rivastigmine, have been
proposed as putative therapeutic agents for TD because some
of the older cholinergic drugs were found to have some
benefit (61). Systematic reviews of these older agents in
Focus Vol. 19, No. 1, Winter 2021
DEBREY AND GOLDSMITH
addition to the newer Alzheimer’s drugs have found limited
overall benefit across studies with nonsignificant trend-level
benefit for active drug compared with placebo (62). Although
one small randomized, placebo-controlled clinical trial
showed no difference for donepezil compared with the con-
trol (63) several case reports (64, 65) and open-label trials (66,
67) have demonstrated benefit for donepezil in the treatment
of TD. One randomized placebo-controlled clinical trial for
galantamine (68) that used a crossover trial design has been
published. It did not find an overall significant benefit for
galantamine in reducing TD symptoms compared with pla-
cebo, although when patients who were initially randomized
to galantamine were crossed over to placebo, they had
worsening of both dyskinesia and parkinsonism.
Limited evidence exists for the efficacy of branched-
chain amino acids, with two open-label trials demonstrating
benefit for the treatment of TD symptoms (69, 70). There
have been three RCTs of Gingko biloba, whose purported
mechanism is via the antioxidant, free-radical scavenging
properties of the extract. A meta-analysis of these trials
showed benefit for Gingko biloba compared with placebo
(71), although larger trials are warranted, as well as further
studies that provide greater mechanistic understanding.
Vitamin E has also been studied, and whereas a recent meta-
analysis of 15 studies showed benefit for vitamin E over
placebo (72), a recent Cochrane Review of the literature
showed no evidence for vitamin E compared with placebo
over 13 RCTs (73). Of note, studies of vitamin E demon-
strated significant publication bias in the meta-analysis,
which may explain the discrepancy in these reviews.
CONCLUSIONS AND FUTURE DIRECTIONS
TD remains a challenging clinical concern for patients
treated with antipsychotic medications. Although the in-
cidence has decreased since the advent of SGAs, the risk of
TD even after treatment with SGAs remains significant. The
impact on quality of life, treatment adherence, and recovery
should not be underestimated. Not only is it important for
prescribing physicians to discuss the risk of TD with patients
who are treated with antipsychotic agents (in addition to
medications such as metoclopramide), but physicians must
be aware of the different treatment options available to treat
these debilitating symptoms.
Clozapine remains an underused treatment option for
TD. It is already underprescribed for patients with persis-
tent symptoms of psychosis, with barriers such as the need
for regular blood monitoring and significant risks of neu-
tropenia and myocarditis, in addition to more common but
concerning side effects (i.e., weight gain, tachycardia, sia-
lorrhea, and constipation). More education on how to safely
and effectively manage these barriers may lead to greater
access to clozapine for patients for whom other antipsy-
chotic medications fail. Should psychiatrists feel more
competent and comfortable prescribing clozapine, its use as
a treatment for TD may be considered. In fact, some have
focus.psychiatryonline.org 21
CURRENT APPROACHES TO TREATMENT OF TARDIVE DYSKINESIA
recommended switching to clozapine monotherapy as an
initial approach to treating TD (35).
The newer VMAT2 inhibitors appear to have the stron-
gest evidence for nonclozapine treatment of TD. Tolerability
and cost appear to be the most common barriers to the use of
these agents. Concern for Qtc prolongation must be con-
sidered, especially if given with antipsychotics or in con-
junction with CYP2D6 inhibitors because all three VMAT2
inhibitors are metabolized via this method. Nevertheless,
these medications appear to offer significant benefit to pa-
tients with debilitating TD.
Other medications that have been studied and reviewed
herein (i.e., clonazepam, amantadine, Gingko biloba) have
limited evidence, although they may have some benefit for
individual patients, especially if those patients cannot tol-
erate or have other contraindications to clozapine or the
VMAT2 inhibitors. Finally, for particularly refractory cases,
surgical and neurostimulatory approaches may be consid-
ered, although most evidence thus far comes from case re-
ports, primarily of tardive dystonia, and thus its benefit for
patients with TD remains unclear.
Future studies are needed to advance our understanding of
the mechanisms underlying TD in order to both develop new,
effective treatment agents and, ideally, discover preventive
approaches. Although progress has been made in recent years
with the current medications, ultimately these medications
target only improvement, which is reversible when medica-
tion is discontinued, as opposed to discovering mechanisms
that may lead to reversal of these debilitating symptoms.
Moreover, greater understanding of underlying risk factors
for TD may lead to predictive algorithms to identify those at
greater risk and help inform physicians’ choice of antipsy-
chotic medication. Despite these gaps in our understanding of
these symptoms, the current pharmacological options, espe-
cially with the more widespread use of the VMAT2 inhibitors,
offer some hope for greater symptomatic improvement that
may lead to greater quality of life and recovery for patients.
AUTHOR AND ARTICLE INFORMATION
Department of Psychiatry and Behavioral Sciences, Emory University,
Atlanta. Send correspondence to Dr. Debrey (sarah.debrey@emory.edu).
The authors report no financial relationships with commercial interests.
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focus.psychiatryonline.org 23
CLINICAL SYNTHESIS
Increasing Psychiatrists’ Role in Addressing the
Cardiovascular Health of Patients With Severe
Mental Illness
Martha Ward, M.D.
The early mortality of individuals with serious mental illness
has long been documented yet persists despite calls for
change. Individuals with serious mental illness have a
higher rate of medical morbidity than those in the general
population across all categories of disease. Cardiovascular
disease is particularly prevalent in this population, and it is
the leading cause of death for persons with serious mental
illness. Addressing cardiovascular risk factors is essential to
closing the mortality gap, yet patients with serious mental
illness often receive poor continuity of medical care, and
Advances in modern medicine have greatly increased the life
span of people living in the United States. However, indi-
viduals living with serious mental illness have been left
behind. A 2003 study revealed that patients with serious
mental illness treated in the US public health sector die, on
average, 25 years earlier than people in the general pop-
ulation (1). Despite multiple calls to action to address this
public health issue, the mortality gap remains, with a recent
meta-analysis estimating that people with schizophrenia
experience an average of 14.5 years of potential life lost (2).
Clearly, further interventions are urgently needed.
Yet finding a solution to this problem is difficult. Reasons
for the mortality gap are complex and multifactorial, in-
volving adverse health behaviors, stigma, medication side
effects, poverty, and psychiatric and cognitive symptom
burden. The situation is compounded by an overwhelming
lack of access to ongoing quality medical care and a sub-
sequent pattern of overuse of emergency services and underuse
of primary care (3). For many people with serious mental ill-
ness, the behavioral health clinic is their only contact with the
medical system, and their psychiatrist is the only physician they
regularly see. In recognizing this reality, the American Psy-
chiatric Association published a position paper in 2015 urging
psychiatrists to play a role in assessing, diagnosing, and treating
the medical problems that contribute to the mortality gap
among people with serious mental illness (4).
24 focus.psychiatryonline.org
psychiatrists are often their only physicians. Thus, to have
an impact on the mortality gap, psychiatrists must address
the cardiovascular health of their patients with serious
mental illness. Here, the author presents a framework of
intervention at varying levels of intensity for psychiatrists to
increase their role in addressing the cardiovascular health of
patients with serious mental illness.
Focus 2021; 19:24–30; doi: 10.1176/appi.focus.20200036
Although rates of disease among people with serious
mental illness exceed those in the general population for
every disease category (1), cardiovascular disease (CVD)
plays a particularly important role in perpetuating the
mortality gap. Rates of cardiovascular risk factors, including
hypertension, tobacco use, obesity, dyslipidemia, and di-
abetes mellitus, are greatly elevated among those with seri-
ous mental illness (5, 6). CVD is two- to threefold more
common among people with serious mental illness and oc-
curs at a younger age (7). Overall, CVD is the most common
cause of death among people with serious mental illness (6).
Because of this, addressing CVD and its risk factors is a
reasonable initial goal for psychiatrists hoping to improve
the medical health of their patients with serious mental
illness.
POTENTIAL INTERVENTIONS FOR PSYCHIATRISTS:
A SLIDING SCALE
Of necessity, interventions initiated by psychiatrists will
exist on a sliding scale, depending on availability of care
referral resources, patient preference, and physician knowl-
edge base. Graduates of combined residency programs (in-
ternal medicine-psychiatry and family medicine-psychiatry)
are ideally situated to provide integrated care to complex
patients with comorbid medical and psychiatric conditions,
Focus Vol. 19, No. 1, Winter 2021

and the recent increase in the number of such programs in
the United States provides hope for improving outcomes
for patients with serious mental illness (8). However, the
number of physicians who complete combined residency
programs is overall minimal compared with patient needs. If
the mortality gap is to be adequately addressed, psychiatrists
who have completed categorical residencies will need to
intervene as well. Comfort with addressing medical health
may require additional training or continuing medical edu-
cation, although primary care skills are increasingly being
emphasized in categorical psychiatry residency training.
Recent psychiatry residency graduates affirm that their
programs have adequately trained them to recognize and
initiate treatment for common medical conditions (9).
Increasing psychiatrists’ comfort with addressing physi-
cal morbidity also requires examination of the therapeutic
frame, boundary crossings, and boundary violations in do-
ing so. According to Freud’s initial description in 1911, the
therapeutic frame consists of certain norms in the patient-
doctor relationship that allow for a safe and contained
structure in which to process communication. Among these
norms is a lack of physical touch. Although a reductionist
and rule-bound adherence to the frame is generally not
helpful to the therapeutic dyad, and handshakes and hugs
are no longer unheard of in the therapeutic relationship,
careful attention to boundary fluidity is necessary. Practice
setting, patient diagnosis, physician expertise, and treatment
modality will all have an impact on the propriety of psy-
chiatrists performing a physical exam to assess their pa-
tients’ physical health status. Risks and benefits must be
carefully weighed. Physical examination is generally not
recommended (outside of obtaining vital signs) in a practice
in which there is no separate examination room and ap-
propriate examination table. Likewise, physical examination
of patients with unstable identity and porous boundaries,
such as those with borderline pathology, may also be harmful
to the therapeutic relationship. The risks of physical exam-
ination are likely much lower for psychiatrists treating pa-
tients solely with medication management. Fortunately, as I
discuss, physical examination is not a necessary component
of many of the interventions that psychiatrists can make to
improve their patients’ medical morbidity and mortality.
TYPES OF INTERVENTION
Psychiatrists’ involvement in their patients’ medical care
will likely cover a large spectrum, depending on multiple
factors. First, psychiatrists will face systemic factors such as
accessibility of primary care providers to consult with or
refer patients to and flexibility in time during psychiatric
visits to allow for interventions. For even the most basic of
interventions, screening, psychiatrists must have access to
on-site laboratory testing and equipment, such as blood
pressure cuffs and scales. Other factors include those in-
trinsic to the patient, such as level of motivation and orga-
nization to follow through with referrals and ability to
Focus Vol. 19, No. 1, Winter 2021
WARD
engage meaningfully in care with a new primary care phy-
sician. Finally, factors intrinsic to the psychiatrist will play a
large role. Motivation, confidence, and belief in the need to
intervene are all necessary qualities to ensure that psychia-
trists address CVD risk among their patients.
SCREENING
At a minimum, psychiatrists should screen their patients
for cardiovascular risk factors. Clear guidelines exist for
screening for metabolic conditions associated with the pre-
scription of second-generation antipsychotics (Table 1) (10).
For patients not prescribed second-generation antipsy-
chotics, screening recommendations for cardiovascular risk
factors vary somewhat depending on organizational guide-
lines. A reasonable paradigm for cardiovascular risk screening
is outlined in Table 2 and incorporates recommendations
from various evidence-based US organizations.
Screening for tobacco use is perhaps the most straight-
forward of the CVD risk factors. Physicians should be cer-
tain to ask about all forms of tobacco (including smoking,
chewing, dipping, and vaping) and whether the patient has
ever used tobacco, because some individuals may not con-
sider themselves smokers if they use tobacco products in-
termittently (11). All adults should be screened annually for
obesity by calculation of body mass index (BMI) (12). BMI is
defined as weight in kilograms divided by the square of the
height in meters. A patient with a BMI of 25–29.9 m/kg2 is
considered overweight, and one with a BMI of $30 m/kg2 is
considered obese. Practitioners must be diligent in avoiding
a judgmental stance concerning weight. Rather than focus
on appearance, physicians must focus solely on the health
risks associated with increasing BMI.
Blood pressure screening is largely noncontroversial and
inexpensive and can easily be done in the office. More reli-
able readings can be done by using a 24-hour ambulatory
blood pressure monitor, but this may be logistically difficult
to set up (12). Daytime blood pressures higher than 130/
80 mmHg are considered positive for hypertension (13).
Screening for elevated lipids should begin at age 40 for
anyone without risk factors for CVD, but physicians could
consider screening as early as age 17 if the patient has sig-
nificant risk factors for CVD. Nonfasting samples are suffi-
cient to determine the need for statin therapy for primary
prevention of CVD.
Screening for diabetes, as for hyperlipidemia, requires
access to laboratory services and is recommended for all
adults ages 18 years or older who have at least one risk factor
for diabetes (see Table 2); for all others, screening is rec-
ommended at age 45. Screening is ideally done by measuring
fasting blood glucose. Values of 100–125 mg/dL indicate
prediabetes, whereas a fasting blood glucose measurement
of 126 mg/dL or more indicates a diagnosis of diabetes. Of
note, glucometers should not be used to diagnose diabetes
because readings may differ by as much as 15% from those
obtained via phlebotomy. If fasting values are unavailable (as
focus.psychiatryonline.org 25
PSYCHIATRISTS AND CARDIOVASCULAR HEALTH OF PATIENTS WITH SEVERE MENTAL ILLNESS

TABLE 1. Monitoring protocol for patients on second-generation antipsychotics the use of motivational in-
Measure Baseline 4 weeks 8 weeks 12 weeks Quarterly Annually terviewing techniques to as-
Personal and family history X X
sess patients’ readiness to
Weighta X X X X X enact change. Inquiries should
Waist circumference X X be nonconfrontational and
Blood pressure X X X encourage collaboration. Once
Fasting blood glucose X X X patients are ready to change
Fasting lipid profile X X X
their behavior, collaborative
a
Body mass index. plans may be enacted using
various cognitive-behavioral
a result of patients’ difficulty with fasting for laboratory exercises. A great deal of evidence supports the use of
collection), hemoglobin A1c (HbA1c) may be used. Values of cognitive-behavioral therapy and mindfulness-based tech-
5.7%26.4% indicate prediabetes, and values of 6.5% or more niques to reduce cardiovascular risk factors, such as obesity
indicate diabetes. Of note, two HbA1c values are required to and tobacco use (15–17). Multiple online resources, texts,
confirm the diagnosis of diabetes mellitus. If any abnormal manuals, and workshops are available to guide such struc-
blood glucose measurements are made, screening should be tured psychological interventions, and some individual ex-
done annually. Among those with normal blood glucose on ercises may be easily incorporated into medication management
screening, repeat screening should occur at 3-year intervals. appointments. These exercises include self-monitoring for
exercise, food intake, and tobacco use; problem solving;
short- and long-term goal setting; and the use of thought
BEHAVIORAL COUNSELING
records and cognitive restricting (18). In addition, psychia-
Although screening is a start, it is not enough. Interventions trists may address external stressors, underlying psychiatric
are essential to have an impact on the mortality gap for pa- disorders, and psychological defenses that may make be-
tients with serious mental illness. Behavioral counseling is havioral change difficult.
highly recommended by the American Health Association to In addition to individual counseling for behavioral change,
decrease overall cardiovascular risk (13). Given that the a robust literature supports group lifestyle interventions
American College of Graduate Medical Education lists psy- for improving cardiovascular risk (19), and a growing body
chotherapy as one of the essential competency milestones of evidence supports the benefits of such interventions for
obtained by psychiatry residents during training (14), it is the population with serious mental illness (20, 21). Psychi-
reasonable to assume that psychiatrists are capable of ef- atrists may take the lead in supporting, promoting, orga-
fectively counseling patients for behavioral change. For nizing, or leading group lifestyle interventions offered in
maximum effectiveness, such counseling should start with their own practice setting. When organizing such interventions,

TABLE 2. Screening guidelines for cardiovascular risk conditions

Risk factor Age (years) Method Frequency
Hypertension $18 Blood pressure measurement (office, Yearly among those with any risk
but preferably 24-hour ambulatory) factor (age $40, overweight or
obesity, African American); every
3–5 years otherwise
Hyperlipidemia 40–75 (may consider earlier screening if Measurement of total cholesterol and Every 5 years
other risk factors are present for high-density lipoprotein (does not
familial hypercholesterolemia or for require fasting)
cardiovascular disease, such as
diabetes mellitus, hypertension,
tobacco use, obesity, chronic kidney
disease, family history)
Tobacco usea $11 Ask about use (including all forms) Annually
Obesity All adults BMIb measurement Annually
Diabetes $18 if BMI is elevated and 1 other risk Fasting blood glucose by blood draw; if Every 3 years if normal; every year if
mellitus factor is present (history of not possible, HbA1cb prediabetic
prediabetes, family history, high-risk
ethnicity, history of gestational
diabetes, cardiovascular disease,
hypertension, dyslipidemia, polycystic
ovarian syndrome, physical
inactivity); $45 for those without risk
factors
a
Per the American Academy of Pediatrics (11).
b
BMI, body mass index; HbA1c, hemoglobin A1c.

26 focus.psychiatryonline.org Focus Vol. 19, No. 1, Winter 2021


psychiatrists may look to the literature to identify elements
associated with greater success; such elements include use
of multiple components (exercise, dietary counseling, and
behavioral therapy), personalization, more frequent contact,
longer duration (longer than three months), manualized
programs, active monitoring (of weight, diet, and exercise),
and training of treatment providers (19). Evidence has
shown that the use of peers (individuals living with serious
mental illness) as treatment team members in lifestyle in-
terventions can also improve outcomes for patients with
serious mental illness (22).
In promoting lifestyle change, psychiatrists must be
mindful to tailor interventions to the life circumstances of
the patients they are treating. For individuals with serious
mental illness, this often means actively addressing adverse
social determinants of health (23). In addition, because in-
dividuals with serious mental illness often experience low
health literacy, low educational attainment, and cognitive
impairment, programs may require simplification of lan-
guage and content (24).
REFERRAL
Astute psychiatrists will recognize when a patient’s medical
needs exceed the care provided in their own practice setting
or when a patient is receiving insufficient medical care
through other providers. Screening and recognizing goals
for improving cardiometabolic risk are both essential pre-
requisites to understanding when to seek a primary or spe-
cialty medical care referral (see Table 3 for treatment goals
for various cardiovascular risk factors). Ideally, a referral to a
primary care provider may occur in a patient-centered
medical home (or a behavioral health home), creating an
integrated care network for the patient. When this is not
possible, it is preferable for psychiatrists to make a facili-
tated referral to a trusted primary care or specialty provider
with whom they have ongoing communication and a good
working relationship. Such physicians may show a greater
aptitude for working with patients with serious mental ill-
ness; sadly, many primary care physicians see patients with
serious mental illness as disruptive, frightening, or time
consuming, and such biases may inhibit formation of a
therapeutic alliance (25). Care managers can be invaluable in
ensuring that patients are able to adhere to primary or
specialty care referral recommendations (26).
For patients with obesity, referral for bariatric surgery
for weight loss may also be warranted. Patients eligible
for referral are those with a BMI of 40 m/kg2 or more and
those with a BMI of 35 m/kg2 or more with obesity-related
comorbid conditions (such as hypertension, diabetes melli-
tus, osteoarthritis, obstructive sleep apnea). Poorly controlled
mental illness is a contraindication to bariatric surgery;
however, patients with serious mental illness who have
stable treatment are eligible for referral. A recent qualitative
study of individuals with obesity and mental illness—many
with serious mental illness—surmised that bariatric surgery
Focus Vol. 19, No. 1, Winter 2021
WARD
was both effective and life changing, although patients may
need additional support in the postoperative period (27).
PHARMACOLOGICAL MANAGEMENT
As prescribers, the initial step for psychiatrists in approaching
the pharmacological management of cardiovascular risk in
patients with serious mental illness may be guided by the
Hippocratic adage “First, do no harm.” The metabolic ef-
fects of psychotropic medications, particularly the second-
generation antipsychotics, are well established. Although
all of the antipsychotics (including the first-generation
agents) have been shown to be obesogenic, weight gain po-
tential varies by individual medication. Among the second-
generation agents, clozapine has the greatest risk, followed
in descending order of magnitude by olanzapine, quetiapine,
risperidone, amisulpride, aripiprazole, and ziprasidone (28).
Weight gained is clinically significant, with an average of
12 kg gained in 40%290% of patients on olanzapine and up
to 31.3 kg gained among patients on clozapine (29). More
recently approved second-generation antipsychotics appear
to be less obesogenic, with asenapine associated with a
0.9-kg weight gain in the first three weeks of treatment and
iloperidone with a 1.5- to 2.1-kg weight gain (29). Medica-
tions used to treat affective disorders (particularly mood
stabilizers) may also cause weight gain. Of patients pre-
scribed valproic acid, 71% gain more than 4 kg, and 20% of
individuals taking lithium gain more than 6.3 kg (29). Anti-
depressants can also induce weight gain. Of patients taking
antidepressants, 10%–20% experience treatment-emergent
increases in weight, with mirtazapine and the tricyclic an-
tidepressants consistently associated with more weight gain
than the selective serotonin reuptake inhibitors (29).
Weight gain resulting from psychotropic medication is
likely due to interactions with a number of neurotransmit-
ters and neural circuits. Mirtazapine and many of the
second-generation antipsychotics (including olanzapine,
quetiapine, and clozapine) are serotonin 2c antagonists; in
mice, serotonin 2c receptor stimulation promotes anorexia,
and mice lacking these receptors become obese. Histamine
may help to centrally regulate satiety, and psychotropic
medications that block the H1 receptor are associated with
TABLE 3. Goals of treatment for cardiovascular risk factors
Risk factor Goal of treatment
Hypertension Blood pressure ,130/80 (except in those $75
years old)
Hyperlipidemia Statin when indicated (if patient has known
cardiovascular disease, chronic kidney
disease, or diabetes mellitus or has a 10-year
atherosclerotic cardiovascular disease risk
of $7.5%)
Tobacco use Cessation
Obesity Body mass index 18.5–24.9
Diabetes mellitus HbA1ca 7.0%–8.0%
a
HbA1c, hemoglobin A1c.
focus.psychiatryonline.org 27
PSYCHIATRISTS AND CARDIOVASCULAR HEALTH OF PATIENTS WITH SEVERE MENTAL ILLNESS
greater weight gain. In addition, anticholinergic effects of
psychotropics may be obesogenic, whether directly through
appetite stimulation or via side effects such as dry mouth
(leading to caloric fluid intake) and sedation (inhibiting
physical activity) (29).
In addition to weight gain, second-generation antipsy-
chotics are associated with lipid and glucose abnormalities.
These metabolic changes are mediated in part by weight gain
but have also been cited independent of adiposity. Olanza-
pine and clozapine confer the greatest risk of lipid abnor-
malities; quetiapine and risperidone confer intermediate
risk. Elevations in triglycerides are most marked, but second-
generation antipsychotics also appear to raise low-density
lipoprotein and total cholesterol. Olanzapine and clozapine
are also associated with the greatest risk of insulin resistance
and glucose dysregulation.
The metabolic syndrome is made up of increased central
adiposity, elevated triglycerides, low high-density lipopro-
tein (HDL), hypertension, and impaired glucose tolerance,
and it is a major risk factor for cardiovascular mortality.
Clozapine, olanzapine, and chlorpromazine are most closely
associated with risk of metabolic syndrome. One meta-
analysis showed a prevalence of metabolic syndrome in ap-
proximately 50% of patients taking clozapine (30).
Those who are most at risk for metabolic abnormalities
(particularly for weight gain) with second-generation anti-
psychotics are younger and treatment naive, although all
patients should be appropriately counseled when starting
psychotropic medications, and a plan for monitoring and
healthy habits should be simultaneously prescribed. To de-
crease cardiovascular risk, polypharmacy should be avoided
when possible, and medication with lower potential for ad-
verse metabolic effects should be considered as initial
therapy. A dose-dependent relationship between metabolic
abnormalities and second-generation antipsychotics has
been suggested, particularly for olanzapine (30). Thus, dose
reductions should be considered and medications tapered to
the lowest therapeutic dose when feasible. In addition,
limited data support starting metformin when treatment
with second-generation antipsychotics is initiated, specifi-
cally those that are more obesogenic (31). Metformin acts by
inhibiting hepatic glucose production and thus has effects on
both weight and glucose regulation. The most common side
effect of metformin is gastrointestinal upset, including di-
arrhea and nausea. To improve tolerability and decrease side
effects, metformin should be started at 500 mg/day and ti-
trated to up to 2,000 mg/day in split doses. Lactic acidosis is
a rare adverse effect of metformin and is more likely to occur
with the accumulation of excess levels. Because metformin is
renally cleared, it is therefore contraindicated for individu-
als with a glomerular filtration rate of less than 30 mL/min
and should be held if an individual is to receive intravenous
contrast dye (32).
When medication-associated metabolic abnormalities do
occur, psychiatrists may consider switching to a psychotro-
pic agent with less metabolic risk while carefully weighing
28 focus.psychiatryonline.org
the potential for psychiatric decompensation. For patients
who have gained more than 7% of pretreatment weight or
have developed hyperglycemia, hyperlipidemia, or hyper-
tension, physical benefits of switching drugs must be given
strong consideration (30). In addition, several medications
have been evaluated as adjunctive strategies for antipsychotic-
induced metabolic abnormalities. For treatment of weight
gain, the largest body of evidence supports the use of met-
formin (6, 33). A smaller body of data shows that the use of
adjunctive aripiprazole, topiramate, reboxitine, or sibutr-
amine is superior to placebo; however, clinically relevant
weight loss (of $7%) was noted only with metformin and
aripiprazole (33). Psychiatrists are generally quite comfort-
able with prescribing the partial D2 antagonist-agonist ari-
piprazole; for a discussion of metformin prescribing, please
see the preceding paragraph.
Limited data support the use of metformin and rosigli-
tazone for improving glucose intolerance (33). Rosiglitazone
is a thiazolidinedione that reduces glucose production and
increases glucose clearance by improving insulin sensitivity
and pancreatic beta-cell function. Rosiglitazone is associated
with fluid retention and liver function abnormalities and is
contraindicated in patients with New York Heart Associa-
tion class III and IV heart failure and those with active liver
disease or increased liver enzymes ($2.5 times the upper
limit of normal). Rosiglitazone should be started at 4 mg/day
and can be titrated to 8 mg/day. Because rosiglitazone may
be associated with mild weight gain and is more likely to
cause hypoglycemia, metformin may be a better initial agent
to prescribe for antipsychotic-emergent glucose dysregula-
tion. In addition, liver enzymes must be monitored among
patients prescribed rosiglitazone (34).
Limited evidence supports the use of metformin, top-
iramate, or sibutramine to treat patients with antipsychotic-
emergent dyslipidemia; in such incidences, these medica-
tions have been shown to decrease both total cholesterol and
triglyceride levels (33). The majority of psychiatrists are
experienced with prescribing the anticonvulsant and mood
stabilizer topiramate, and the logistics of metformin pre-
scribing have previously been listed. Sibutramine is a se-
lective reuptake inhibitor of serotonin, norepinephrine, and,
to a lesser extent, dopamine. Sibutramine was approved as a
weight loss medication by the Food and Drug Administra-
tion in 1997 but was pulled from the US market in 2010 be-
cause of an association with cardiovascular events.
In addition to prescribing medications to counteract ad-
verse effects of second-generation antipsychotics, psychia-
trists may elect to provide evidence-based pharmacological
treatment for medical conditions associated with increased
cardiovascular risk. In particular, pharmacological assis-
tance with tobacco cessation greatly improves patients’
ability to successfully quit smoking. Therapies approved by
the Food and Drug Administration for smoking cessation
include nicotine replacement therapy (NRT), bupropion,
and varenicline (35); all three medications have been shown
to improve success in nicotine cessation among patients with
Focus Vol. 19, No. 1, Winter 2021

serious mental illness without worsening psychiatric
symptoms (36). NRT provides controlled doses of nicotine
without the harmful substances found in tobacco products.
It improves withdrawal symptoms but does not alleviate
them completely because the release of nicotine into the
central nervous system is much more gradual than with
cigarette inhalation. NRT is available in many formulas, in-
cluding patches, gum, oral and nasal sprays, lozenges, and
inhalers. NRT can safely be used while patients are still using
tobacco products; the instruction for patients not ready to
quit should be to cut back as much as possible while using
NRT. Dosing of NRT should correlate to the amount of to-
bacco used in a day. For example, when prescribing nicotine
patches, anyone smoking 10 or more cigarettes per day
should be prescribed a 21-mg patch. Basal delivery formu-
lations (the patch) may also be combined with quick-release
formulations (such as gum) to combat cravings. Nicotine
patches may cause skin irritation and so should be avoided
among patients with chronic dermatologic conditions. To
reduce skin irritation, patients should be instructed to place
the patch on a different area of the skin each day.
Psychiatrists are likely familiar with prescribing bupro-
pion for patients with depression. Bupropion is a norepi-
nephrine and dopamine reuptake inhibitor that may also act
as a nicotine receptor antagonist. Bupropion should be
prescribed for at least seven days before the quit date for
tobacco cessation in order to build up therapeutic serum
levels. Varenicline is a partial agonist of nicotinic acetyl-
choline receptors (with strongest affinity for alpha4beta2
receptors) and a full agonist of the serotonin type 3 recep-
tors. Varenicline is believed to assist with withdrawal
symptoms via its agonism of the nicotinic receptor and to
prevent the reward of smoking via competitive inhibition of
nicotine binding. As with bupropion, varenicline should be
started one week before cessation attempt; titrating slowly
can improve gastrointestinal side effects (as can taking the
medication with a full glass of water). Combination therapy
with NRT and bupropion may lead to greater success in
quitting tobacco use (35). Electronic cigarettes (e-cigarettes)
have gained in popularity in recent years; however, a recent
review found no evidence that e-cigarette use is associated
with increased tobacco cessation for cigarette smokers (37).
In addition, recent studies show that dual use of e-cigarettes
and tobacco products may be associated with greater risk of
cardiovascular disease (38).
Although a thorough discussion of the evidence-based
treatment of other disorders associated with increased car-
diovascular risk is outside the scope of this article, psychiatrists
may increase their knowledge, comfort, and competency in
prescribing by following treatment guidelines and pursuing
continuing medical education opportunities.
INTERVENTIONS AT THE SYSTEMS LEVEL
Although addressing the medical health of individual pa-
tients is important, systems-level change is also needed.
Focus Vol. 19, No. 1, Winter 2021
WARD
Psychiatrists are optimally situated to advocate for such
changes. At the health system level, psychiatrists may act as
champions of integrated health care initiatives. Integrated
care settings improve coordination of care and have the
potential to change care utilization patterns and, ultimately,
health outcomes. Positive findings may be disseminated to
allow for successful replication in other settings. Psychia-
trists may also create and disseminate guidelines for the
coordinated medical and psychiatric care of their patients.
At the societal level, psychiatrists can lead or join stigma-
reducing initiatives to change the way communities and
health care systems view individuals with serious mental
illness. They can advocate for policy changes that remove
discriminatory laws, invoke mental health parity, strengthen
existing health care platforms, and increase funding for
public health and the social safety net (21, 39).
CONCLUSIONS
CVD is the leading cause of death for individuals with seri-
ous mental illness. To improve medical morbidity and close
the mortality gap, cardiovascular risk must be addressed. In
their role as trusted physicians for patients with serious
mental illness, psychiatrists are well situated to address their
patients’ holistic health, and they are often the default pri-
mary health care provider for such patients. Comfort and
knowledge will dictate psychiatrists’ appropriate level of
intervention for cardiometabolic conditions, although screen-
ing and addressing psychotropic-associated side effects is
commonly considered standard of care. However, address-
ing cardiovascular risk among individual patients is not
sufficient to close the mortality gap. Medical illness among
persons with serious mental illness exceeds that among the
general population across every disease category. Preventive
health measures, such as vaccinations and age-appropriate
cancer screening, must also be a priority. Ongoing care of
complex medical multimorbidity must be made available.
Changes at the health care system and societal levels are
ultimately needed. The time has come for psychiatrists to
stand up as leaders in prioritizing the overall health of in-
dividuals living with serious mental illness.
AUTHOR AND ARTICLE INFORMATION
Department of Psychiatry and Behavioral Sciences and Department of
Medicine, Emory University School of Medicine, Atlanta. Send corre-
spondence to Dr. Ward (mcraig@emory.edu).
Dr. Ward receives royalties from UpToDate.
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Focus Vol. 19, No. 1, Winter 2021

Novel Formulations of ADHD Medications: Stimulant
Selection and Management
Ann C. Childress, M.D.
Attention-deficit hyperactivity disorder (ADHD) is the most
commonly diagnosed psychiatric disorder in children and
adolescents in the United States. In 2016, approximately 3.8
million U.S. children ages 2 to 17 years with ADHD were
being treated with medication. There are approximately 30
different amphetamine (AMPH) and methylphenidate (MPH) for-
mulations on the market. These include immediate-release and
extended-release compounds. The extended-release formula-
tions contain various ratios of immediate-release and extended-
release components, which determine the pharmacokinetic
Attention-deficit hyperactivity disorder (ADHD) is the most
commonly diagnosed psychiatric disorder in children, and
symptoms often continue into adulthood (1–3). Among U.S.
children ages 2 to 17, approximately 6.1 million (9.4%) were
estimated to have been diagnosed as having ADHD on the
basis of the 2016 National Survey of Children’s Health (4).
Of these, 62.0% (approximately 3.8 million) with current
ADHD symptoms were taking medication. The estimated
prevalence of ADHD among U.S. adults is 4.4% (3). The
prevalence of adult ADHD medication use in the total U.S.
population was 1.48% in 2010—the highest in the world (5).
Several professional societies in the United States, including
the American Academy of Pediatrics (AAP), the American
Academy of Child and Adolescent Psychiatry (AACAP), and the
Society for Developmental and Behavioral Pediatrics (SDBP),
have released guidelines for the treatment of ADHD in children
and adolescents. Although organizations in other countries,
such as the National Institute for Health Care and Excellence,
have also published ADHD treatment guidelines, this article
focuses on recommendations for treatment and medications
available in the United States (6).
Key action statement 5b in the recent AAP “Clinical
Practice Guideline for the Diagnosis, Evaluation, and Treat-
ment of ADHD in Children and Adolescents” states that ele-
mentary school– and middle school–age children should be
treated with a U.S. Food and Drug Administration (FDA)–
approved medication, along with parent training in behav-
ior management (7). Key action statement 5c states that
Focus Vol. 19, No. 1, Winter 2021
CLINICAL SYNTHESIS
(PK) profile. For stimulants, the PK and pharmacodynamic (PD)
profiles are tightly linked, and the immediate-release and
extended-release percentages influence onset and duration
of drug effects. Choosing the right stimulant medication for a
patient depends on an understanding of the PK/PD profile, the
time of day that symptoms are most impairing, the need for
morning and evening symptom control and individual patient
preferences.
Focus 2021; 19:31–38; doi: 10.1176/appi.focus.20200032
adolescents should be prescribed FDA-approved medications
for ADHD, with the adolescent’s assent, and encourages the
primary care provider to also prescribe evidence-based training
or behavioral interventions along with appropriate educational
interventions. For preschool-age children (ages 4 to ,6), key
action statement 5a recommends evidence-based parent train-
ing in behavior management. If parent training in behavior
management is not available or is available and not effective,
treatment with methylphenidate is recommended.
The SDBP issued a practice guideline for the assessment
and treatment of complex ADHD in children and adoles-
cents in February 2020 (8). It recommends evidence-based
treatments for ADHD and coexisting conditions.
Although the AACAP “Practice Parameter for the Assess-
ment and Treatment of Children and Adolescents With At-
tention-Deficit/Hyperactivity Disorder ” was published more
than a decade ago, it is still relevant (9). It recommends initial
pharmacological treatment with an FDA-approved medication.
FDA-approved medications include stimulants and non-
stimulants. Stimulants include amphetamine (AMPH) and
methylphenidate (MPH). Nonstimulants include atomoxetine,
guanfacine extended release, and clonidine extended release
(10–14).
DRUG REVIEW
Stimulants are by far the most widely prescribed medica-
tions for the treatment of ADHD in the United States (15).
focus.psychiatryonline.org 31
NOVEL FORMULATIONS OF ADHD MEDICATIONS
Thus this article focuses on the use of stimulants to treat
ADHD, specifically how to target specific patient needs. Al-
though osmotic-release oral system (OROS) MPH (Concerta),
mixed amphetamine salts (Adderall), mixed amphetamine
salts extended release (Adderall XR), and lisdexamfetamine
(Vyvanse) have the largest market share in the United States,
stimulant formulations prescribed less frequently should also
be considered when treating individual patients (15).
Approximately 30 stimulants are FDA-approved for the
treatment of ADHD, and 12 of these have been approved
since 2010. New stimulant formulations approved since 2010
include MPH extended-release oral suspension (Quillivant
XR), MPH extended-release chewable tablets (QuilliChew
ER), racemic AMPH (Evekeo), racemic AMPH orally dis-
integrating tablets (Evekeo ODT), multilayer-release MPH
(Aptensio XR), AMPH extended-release oral suspension 2.5
mg/mL (Dyanavel XR), MPH extended-release orally dis-
integrating tablet (Cotempla XR-ODT), AMPH extended-
release orally disintegrating tablets (Adzenys XR-ODT), AMPH
extended-release oral suspension 1.25 mg/mL (Adzenys ER),
mixed amphetamine salts 16 hour (Mydayis), MPH delayed-
release and extended-release (Jornay PM), and MPH multilayer-
release 16 hour (Adhansia XR) (16–26). AMPH immediate release
(Zenzedi) is not a new formulation but includes multiple dex-
troamphetamine doses not previously available (27). Medica-
tions approved since 2000 are listed in Tables 1 and 2.
Stimulant formulations not mentioned above include ra-
cemic MPH controlled delivery (Metadate CD), MPH long
acting (Ritalin LA), Methylin, and Methylin ER (28–30).
Methylin is an oral suspension of MPH immediate-release
formulation, and Methylin ER is bioequivalent to Ritalin SR.
Ritalin SR has been shown to have efficacy from approxi-
mately 1 hour to 9 hours after dosing (31). MPH transdermal
system (Daytrana), a patch placed on the hip that delivers
MPH through the skin, is also marketed (32). Dexmethyl-
phenidate, the d-threo enantiomer of racemic MPH, is marketed
as Focalin, dexmethylphenidate extended release (Focalin XR),
and multiple generics (33, 34).
Stimulants exhibit a strong concentration-response re-
lationship for both efficacy and safety (35–37). For this
reason, different formulations with different pharmacoki-
netic profiles developed from the same active component
(AMPH or MPH) may have differing onset and duration of
effect.
How to Choose a Stimulant Formulation
With the vast number of medications available to treat
ADHD, selecting an initial pharmacological treatment may
seem complex. However, the array of available medications
allows the clinician to tailor treatment to individual patient
needs. When choosing an initial therapy for ADHD, one
should first consider that stimulants are in general more
effective than nonstimulants (38). Other factors, such as the
time of day when a patient is most symptomatic, the ability
to swallow a tablet or capsule, concern about abuse or di-
version either with the patient or a household member, and
32 focus.psychiatryonline.org
patient or parent preference, should also be considered.
Daytime functioning or evening commitments should also
influence the formulation choice. In general, when choos-
ing a stimulant, an extended-release formulation should be
chosen in lieu of an immediate-release formulation to im-
prove adherence and decrease the risk of misuse (39, 40).
A recent meta-analysis of efficacy and tolerability of ADHD
medications in children, adolescents, and adults favored the
use of MPH in children and adolescents and AMPH in adults
as initial pharmacological treatment for ADHD (41). FDA-
approved drugs evaluated also included guanfacine extended
release and atomoxetine.
Is the Patient Able to Swallow Tablets or Capsules?
Although the extended-release stimulant capsule formula-
tions can be opened and sprinkled on applesauce for patients
who cannot or prefer not to swallow a capsule whole, this
maneuver is more difficult than it sounds. Capsules must
be opened carefully to avoid spilling the contents, and it is
important that the patient not chew the contents to avoid
premature release of the drug (dose dumping). For patients
who cannot or will not swallow an intact tablet or capsule, it
may be more practical to choose an extended-release suspen-
sion in a chewable or orally disintegrating tablet formulation. It
is important to consider patient and parent preference, in-
cluding taste, when choosing a preparation. For example, teens
may prefer not to take a suspension. Suspensions may also be
less transportable than tablets or capsules, and MPH extended-
release oral suspension is dispensed in a glass bottle that can
break if dropped.
Oral suspensions can be easily titrated with just one
prescription. The directions contained in the package inserts
allow quick titration to optimal dose: MPH extended-release
oral suspension (10–20 mg weekly), AMPH extended-
release oral suspension 1.25 mg/mL (3.1–6.3 mg weekly),
and AMPH extended-release oral suspension 2.5 mg/mL
(2.5–10 mg every 4 to 7 days), so that patients can escalate to
an effective dose within 1 month of starting medication. In
contrast, for patients who have difficulty tolerating stimu-
lant increases with tablets or capsules, the medication can be
titrated very slowly with an oral suspension. Dosage can
easily be adjusted by less than a mL to allow time for at-
tenuation of adverse effects.
How to Achieve Optimal Response
Dose optimization of medication is important when treating
ADHD. In double-blind, placebo-controlled clinical studies
using one stimulant, 25%235% of subjects were considered
nonresponders (9). However, in crossover studies compar-
ing AMPH with MPH, 68%297% of subjects responded to at
least one class of stimulants and 12%271% responded to
both (42).
How, then, does a clinician maximize the opportunity for
response? A standardized scale should be used to obtain
baseline and follow-up ADHD symptom ratings. For chil-
dren, adolescents, and adults, several scales are available. A
Focus Vol. 19, No. 1, Winter 2021
 CHILDRESS

TABLE 1. Extended-release methylphenidate formulations approved since 2000 for the treatment of attention-deficit hyperactivity
disorder
Maximum
Onset of duration Initial
Formulation Dose form effecta of effecta dose Dosing
Methylphenidate 25-, 35-, 45-, 55-, 70-, 1.0 hour 16 hours 25 mg 25–85 mg; increase
multilayer release, 85-mg capsules 10–15 mg every
extended release 5 days
(Adhansia XR)
Methylphenidate 10-, 15-, 20-, 30-, 40-, 1.0 hour 12 hours 10 mg 10–60 mg; increase
multilayer release 50-, 60-mg by 10 mg every
(Aptensio XR) capsules 7 days
Osmotic-release 18-, 27-, 36-, 54-mg 1.0 hour 12.5 hours 18 mg 18–54 mg for
oral system tablets children; 18–72 mg
methylphenidate for adolescents and
(Concerta) adults (not to
exceed 2 mg/kg/
day)
Methylphenidate 8.6-, 17.3-, 25.9-mg 1.0 hour 12 hours 17.3 mg 17.3–51.8 mg;
extended release, tablets increase 8.6
orally disintegrating –17.3 mg/day every
tablet (Cotempla 7 days
XR-ODT)
Methylphenidate 10-, 15-, 20-, 30-mg 2.0 hours 12 hours (when worn 10 mg 10–30 mg
transdermal system patches for 9 hours)
(Daytrana)
Dexmethylphenidate 5-, 10-, 15-, 20-, 25-, 0.5 hour 12 hours 5 mg for children; 5–30 mg for children;
extended release 30-, 35-, 40-mg 10 mg for adults 10–40 mg for
(Focalin XR) capsules adults
Methylphenidate 20-, 40-, 60-, 80-, 10 hours after 23 hours after dosing 20 mg 20–100 mg; increase
delayed release/ 100-mg capsules dosing 20 mg weekly
extended release
(Jornay PM)
Methylphenidate 10-, 20-, 30-, 40-, 1.5 hours 7.5–12 hours 20 mg 10–60 mg
controlled delivery 50-, 60-mg (depending on
(Metadate CD) capsules dose)
Methylphenidate Extended-release 0.75 hour 12 hours 20 mg 20–60 mg; increase
extended release, suspension 25 mg/ 10–20 mg every
oral suspension 5 mL 7 days
(Quillivant XR)
Methylphenidate 20 mg-, 30 mg-, 2.0 hours 8 hours 20 mg 20–60 mg; increase
extended release, 40-mg tablets 10–20 mg every
chewable tablet 7 days
(QuilliChew ER)
Long-acting 10-, 20-, 30-, 40-mg 30 minutes 12 hours (depending 10–20 mg 10–60 mg
methylphenidate capsules on dose)
(Ritalin)
a
Data for onset and duration of effect may not be in the Food and Drug Administration–approved label.

clinician should choose one for children and adolescents and
another for adults to use regularly. Most laboratory class-
room studies used an open-label, dose-optimization design
prior to the double-blind, placebo-controlled classroom
period. For several studies, a 30% improvement on an ADHD
rating scale and a Clinical Global Impression improvement
score of 1 (very much improved) or 2 (much improved) were
considered minimal criteria for optimal response. Many
protocols allowed further dose increases if tolerability was
acceptable and subjects could benefit from an increased
dose. If subjects had difficulty tolerating the higher dose, a
dose reduction was allowed. Additionally, if subjects could
not achieve the above criteria, they were discontinued from
the trial. These criteria should be considered when treating
patients in clinical practice. If a patient is unable to reach or
tolerate an optimal dose in practice, the drug should be
discontinued and another formulation prescribed.
Target Specific Times of Day
Early-morning efficacy. The time of day when symptoms are
most impairing can be targeted with stimulant formulations.
If a child or adult has severe problems in the morning that
cause difficulty preparing for school or work, a medication
that is effective in the morning can be chosen. For example,
delayed-release/extended-release MPH is formulated to have
delayed onset of effect for approximately 10 hours after in-
gestion and is designed for patients to take in the evening and
have onset of effect upon awakening the next morning. Data

Focus Vol. 19, No. 1, Winter 2021 focus.psychiatryonline.org 33

NOVEL FORMULATIONS OF ADHD MEDICATIONS

TABLE 2. Intermediate- and extended-release amphetamine formulations approved since 2000 for the treatment of attention-deficit
hyperactivity disorder
Maximum
Onset of duration Initial
Formulation Dose form effecta of effecta dose Dosing
Mixed amphetamine 5-, 10-, 15-, 20-, 25-, 1.5 hours 12 hours (depending 10 mg for ages 6–17; 5–30 mg for ages 6
salts, extended 30-mg capsules on dose) 20 mg for adults –12; 5–20 mg for
release (Adderall ages 13–17; 20 mg
XR) for adults
Extended-release 3.1-, 6.3-, 9.4-, 12.5-, Bioequivalent to Bioequivalent to 6.3 mg for ages 6–17; 6.3–18.8 mg for ages
amphetamine, 15.7-, 18.8-mg Adderall XR Adderall XR 12.5 mg for adults 6–12; 6.3–12.5 mg
orally disintegrating tablets for ages 13–17;
tablets (Adzenys XR 12.5 mg for adults
ODT)
Extended-release 1.25-mg/mL Bioequivalent to Bioequivalent to 6.3 mg for ages 6–17; 6.3–18.8 mg for ages
amphetamine, extended-release Adderall XR Adderall XR 12.5 mg for adults 6–12; 6.3–12.5 mg
suspension suspension for ages 13–17;
(Adzenys ER) 12.5 mg for adults
Amphetamine, 2.5-mg/mL 30 minutes 13 hours 2.5–5 mg for ages 2.5–20 mg for ages
extended release, extended-release 6 and older 6 and older;
oral suspension suspension increase 2.5–5 mg
(Dyanavel XR) every 4–7 days
Racemic 5-, 10-mg tablets 45 minutes 10 hours 2.5 mg for ages 3 and 5–40 mg divided
amphetamine older; 5 mg for daily or twice daily
(Evekeo) ages 6 and older for ages 6 and
older
Racemic 5-, 10-, 15-, 20-mg Bioequivalent to Bioequivalent to 5 mg daily or twice Increase 5 mg
amphetamine, tablets Evekeo Evekeo daily weekly; maximum
orally disintegrating dose not listed in
tablets (Evekeo label
ODT)
Mixed amphetamine 12.5-, 25-, 37.5-, 2.0 hours 16 hours 12.5 mg for ages 12.5–25 mg for ages
salts, extra-long 50-mg capsules 13 and older 13–17; 12.5–50 mg
extended release for adults
(Mydayis)
Lisdexamfetamine 10-, 20-, 30-, 40-, 1.5 hours 14 hours in adults; 30 mg 30–70 mg; increase
(Vyvanse) 50-, 60-, 70-mg 13 hours in children 10–20 mg weekly
capsules; 10-, 20-,
30-, 40-, 50-,
60-mg chewable
tablets
a
Data for onset and duration of effect may not be in the Food and Drug Administration–approved label.

from two studies enrolling subjects ages 6 to 12 years who
had morning impairment showed significant improvement
in completing the morning routine. A laboratory classroom
study demonstrated that the drug was effective, compared
with placebo, during the school day and into the evening. An
important consideration with delayed-release/extended-release
MPH is dosing. The relative bioavailability of delayed-release/
extended-release MPH is 73.9%, compared with immediate-
release MPH (43). At the end of a 6-week, open-label, dose-
optimization period in one study, the mean daily optimized
dose was 66.2 mg (SD519.56) (44). Although the FDA-
recommended starting dose is 20 mg, most patients will not
achieve optimal symptom control until higher doses are
prescribed. For example, a patient taking 72 mg of OROS-
MPH may need to take 100 mg of delayed-release/extended-
release MPH.
For patients with early-morning impairment who prefer
not to take medication in the evening, two extended-release
formulations have demonstrated onset of efficacy at 30 minutes
after dosing. These include dexmethylphenidate extended-
release and AMPH extended-release oral suspension 2.5 mg/mL
(45, 46). Additionally, MPH extended-release oral suspension
has onset of effect at 45 minutes after dosing (47). Onset of
effect is influenced by the percentage of immediate-release
compound in different formulations. For example, OROS-
MPH is composed of 22% immediate-release MPH, whereas
MPH controlled delivery contains 30% immediate-release
MPH and MPH long acting and dexmethylphenidate extended
release have a 50% immediate-release component. Although
MPH extended-release oral suspension contains approxi-
mately 20% MPH immediate release and 80% MPH extended
release, there are thousands of MPH particles in each dose.
The extended-release particles are covered by a proprietary
coating of various thicknesses to achieve early onset and ex-
tended duration of effect (47).
OROS-MPH has 22% MPH immediate-release coating on
the tablet, and the label states that OROS-MPH did not have
significant change from placebo in a laboratory classroom

34 focus.psychiatryonline.org Focus Vol. 19, No. 1, Winter 2021


trial until 2 hours after dosing (13). A head-to-head trial
between OROS-MPH and MPH controlled delivery dem-
onstrated that OROS-MPH has an earlier onset of effect,
with an effect size of 0.52 at 1.5 hours postdose (48). A later
trial, measuring time points from 1 hour to 12.5 hours after
dosing, demonstrated onset of efficacy at 1 hour and duration
of effect to 12.5 hours, compared with placebo (49).
Another option is to apply the MPH transdermal system to
the hip before the patient awakens; however, this approach
requires a caregiver to be up early to apply the patch because
it takes about 2 hours to onset of effect (50). Because it is
recommended to wear the patch for no more than 9 hours,
application early in the morning would likely require removal
and proper disposal by the child at school. For example, if the
MPH transdermal system is applied at 0400, it should be
removed at 1300. Because more than 50% of MPH drug
content remains in the patch after removal at 9 hours, the
potential for misuse exists for discarded patches (51).
Evening efficacy. Multiple marketed extended-release for-
mulations have been shown to be effective 12 hours post-
dose, as measured in a laboratory classroom, after the drug
has been optimized over several weeks. It is important to
remember that drug effects are compared with placebo ef-
fects in the laboratory classroom trials. In an examination of
one such effect—dexmethylphenidate 20 mg at 12 hours—
ratings were similar to predose but significantly better than
placebo ratings. This is an example of a statistically signifi-
cant but not clinically relevant outcome. Consequently, many
patients may require the addition of an afternoon immediate-
release formulation to achieve noticeable efficacy at 12 hours
and beyond.
To avoid use of multiple medications for patients who
require a longer duration of effect, one MPH extended-
release and three AMPH extended-release formulations are
available. Laboratory classroom studies in adults demonstrated
duration of effect of up to 16 hours for dose-optimized MPH
extended-release and mixed amphetamine salts extended-
release formulations (52, 53). The duration of effect for lis-
dexamfetamine in laboratory classroom trials was shown to
be 13 hours in children ages 6 to 12 and 14 hours in adults (54,
55). In another laboratory classroom trial, AMPH extended-
release oral suspension 2.5 mg/mL also showed efficacy to
13 hours (56).
Because lisdexamfetamine is a prodrug and the l-lysine
has to be cleaved from the dextro-amphetamine for the drug
to become active, its onset of effect is delayed. In a laboratory
classroom study in children ages 6 to 12, onset of effect oc-
curred approximately 1.5 hours after ingestion (55). In the
mixed amphetamine salts 16-hour trials, the first onset of
effect was measured at 2 hours after dosing in an adolescent
laboratory classroom (57).
In addition to differences in onset and duration of effect,
formulations differ in the time of peak efficacy and the
amount of interpatient variability. Many of the extended-
release properties depend on pH in different segments of the
Focus Vol. 19, No. 1, Winter 2021
CHILDRESS
gastrointestinal (GI) tract. GI transit time can influence re-
lease of the extended-release portion of the drug and shorten
or lengthen the duration of efficacy. Food can delay onset of
effects for many formulations and shorten it for others (37).
For example, administration with a high-fat meal delayed
time to maximum concentration (Tmax) by 1 hour for OROS-
MPH and by 2.5 hours for mixed amphetamine salts ex-
tended release and shortened Tmax by 30 minutes for MPH
extended-release orally disintegrating tablet (37). Maximum
concentration of the active moiety may also be decreased
when administered with a high-fat meal.
Few head-to-head studies have evaluated extended-release
stimulants. In two studies comparing dexmethylphenidate
extended release with OROS-MPH, the dexmethylphenidate
extended-release formulation had a faster onset of effect,
whereas OROS-MPH showed greater effect at 10–12 hours
(58, 59). When controlled-delivery MPH was compared
with OROS-MPH, both were significantly better statistically,
compared with placebo, from 1.5 to 7.5 hours (48). The MPH
controlled-delivery effect was statistically better, compared
with OROS-MPH, at 1.5–4.5 hours, whereas the OROS-MPH
effect was statistically better, compared with MPH controlled
delivery, at 12 hours (48). Direct comparisons of other MPH
products have not been conducted.
Extend Duration of Effect
When prescribing a stimulant, it is important to understand
that increasing the dose can prolong duration of efficacy.
This is illustrated by the trial comparing 20 mg dexmethyl-
phenidate extended release with 30 mg dexmethylphenidate
extended release. Attempted and correct scores on a math
test were higher for the patients on the 30 mg dose at 10–12
hours (60). Mixed amphetamine salts extended release is
another example. In the mixed amphetamine salts extended-
release laboratory classroom trials, onset of effect was seen
by 1.5 hours after dosing (61). However, only the 20- and
30-mg doses were effective at 10.5 and 12 hours after dosing.
Although extended duration of effect is seen in trials, it may
not be seen clinically. If a patient is tolerating a specific dose
of medication but the dose is not fully optimized, increasing
the dose may be a consideration. Adverse effects should be
queried before and after the dose increase to ensure that an
attempt at extending the efficacy does not make the drug
side effects intolerable.
Single-Isomer Versus Racemic Formulation
Another consideration in treatment is whether to use a single
isomer or a racemic formulation. With MPH, the d-threo-
enantiomer preferentially crosses the blood-brain barrier.
Plasma concentrations are ten to 40 times higher than those
of the l-enantiomer (62). When dexmethylphenidate is used,
the dose used is half of the racemic drug. Theoretically, one
might expect fewer adverse effects with the single d-enantiomer;
however, no data available support this notion—adverse ef-
fects are similar for dexmethylphenidate and racemic MPH
in clinical trials.
focus.psychiatryonline.org 35
NOVEL FORMULATIONS OF ADHD MEDICATIONS
In contrast, for AMPH, both the both the d- and l- isomers
are effective in treating ADHD (63). Both isomers increase
the extracellular concentrations of dopamine and norepinephrine
in the brain. Currently, only d-AMPH and d,l-AMPH prepara-
tions are on the market. The d,l-AMPH preparations contain d-
and l-isomers in a ratio of 50:50 (racemic AMPH and racemic
AMPH orally disintegrating tablets) or in a ratio of 3:1 (mixed
amphetamine salts, AMPH extended-release oral suspen-
sion, AMPH extended-release orally disintegrating tablet,
and AMPH extended-release oral suspension) (14, 64–66).
AMPH extended-release orally disintegrating tablets and
AMPH extended-release oral suspension 1.25 mg/mL are
bioequivalent to mixed amphetamine salts extended release;
however, AMPH extended-release orally disintegrating tab-
lets and AMPH extended-release oral suspension do not con-
tain salt molecules, and their doses are described only as
AMPH base.
In 2013, the FDA began to require all newly approved
stimulant formulations to express dose of the active moiety
rather than the salt form (67). Although the directive was
meant to decrease confusion, the goal has not been accom-
plished. For example, mixed amphetamine salts extended-
release 30 mg is equivalent to 18.8-mg AMPH extended-release
orally disintegrating tablets or AMPH extended-release oral
suspension 1.25 mg/mL, and MPH hydrochloride 30 mg is
equivalent to 25.9-mg MPH extended-release orally dis-
integrating tablets (68, 69). Multiplying the dose of MPH hy-
drochloride extended-release products by 0.8647 will result
in the appropriate dose of MPH extended-release orally dis-
integrating tablets. Because the conversion factor for AMPH
extended-release orally disintegrating tablets depends on the
molecular weight of the AMPH salt and because marketed
AMPH products vary in their salt composition, the reader is
referred to the table in Engelking et al. (67) for the appropriate
conversion factors.
Regarding the AMPH orally disintegrating tablets and
AMPH extended-release suspension 1.25 mg/mL, 50% of
AMPH microparticles are coated for delayed release and
50% are left uncoated for the immediate-release component
(69). Although bioequivalent to mixed amphetamine salts
extended release, the properties of the orally disintegrating
tablets and suspension dosage forms may make these for-
mulations more tolerable for individual patients. With mixed
amphetamine salts extended release, half of the drug is re-
leased immediately and half approximately 4 hours later
(64). AMPH extended-release oral suspension 2.5 mg/mL is
bioequivalent to two doses of mixed amphetamine salts ex-
tended release dosed 4 hours apart but is also formulated
with immediate-release and extended-release microparti-
cles and no salt—and doses are described in mg of AMPH
base.
Racemic AMPH is intermediate acting. A single dose mea-
sured in a laboratory classroom demonstrated onset and du-
ration of effect at 45 minutes and 10 hours, respectively (70).
Racemic AMPH orally disintegrating tablets are bioequivalent
to racemic AMPH and are expected to have similar onset and
36 focus.psychiatryonline.org
duration, but this formulation has not been evaluated in a
laboratory classroom (71). These drugs are often dosed twice
daily, 4 to 6 hours apart (67, 72).
Dextro-AMPH is marketed in multiple immediate-release
preparations and also as the extended-release prodrug lis-
dexamfetamine. The immediate-release formulation of dextro-
AMPH is dosed two to three times daily (73, 74).
CONCLUSIONS
Multiple MPH and AMPH drugs are available for the treat-
ment of ADHD, and the pharmacokinetic and pharmaco-
dynamic properties of various formulations are tightly
linked. Choosing the most appropriate medication depends
on time of day when symptom control is needed, tolerability,
and individual preferences. Small differences in the ratio
of immediate-release to extended-release drug may translate
to significant differences in onset and duration of effect. It
is important have a thorough understanding of the entire
ADHD armamentarium to provide the best care for patients.
AUTHOR AND ARTICLE INFORMATION
Center for Psychiatry and Behavioral Medicine, Inc., Las Vegas. Send
correspondence to Dr. Childress (drann87@aol.com).
Dr. Childress reports receipt of research or writing support, participation
on advisory boards, and service as a consultant or speaker for Adlon
Therapeutics, Aevi Genomic Medicine, Akili Interactive, Allergan, Arbor
Pharmaceuticals, Cingulate Therapeutics, Emalex Biosciences, Iron-
shore Pharmaceuticals, Jazz Pharmaceuticals, KemPharm, Lundbeck,
Neos Therapeutics, Neurovance, NLS Pharma, Otsuka, Pearson, Pfizer,
Purdue Pharma, Rhodes Pharmaceuticals, Sunovion, Supernus Phar-
maceuticals, Takeda, and Tris Pharma.
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Focus Vol. 19, No. 1, Winter 2021

Treatment of Hypoactive Sexual Desire Disorder
Among Women: General Considerations and
Pharmacological Options
Gabriela S. Pachano Pesantez, M.D., and Anita H. Clayton, M.D.
Hypoactive sexual desire disorder (HSDD) is a persistent or
recurrent absence of sexual fantasies and desire for sexual
activity, causing marked personal distress or interpersonal
difficulties. HSDD affects 10% of U.S. women and is associated
with depression and other negative emotional states. It is
imperative that psychiatrists are competent to make this
diagnosis and are aware of available treatment options. A full
psychiatric and medical history are necessary to identify
potential causes or contributing factors that may need to be
addressed first. The authors discuss the diagnostic tools
Hypoactive sexual desire disorder (HSDD) is defined in the
DSM-IV-TR as a persistent or recurrent absence of sexual
fantasies and desire for sexual activity, which causes marked
personal distress or interpersonal difficulties. The symptoms
are not better explained by another axis I diagnosis and
are not due to the direct physiological effects of a drug
or medical condition. It is further classified into lifelong
or acquired, and generalized or situational (1). The Inter-
national Society for the Study of Women’s Sexual Health
developed a definition for HSDD that states that either a lack
of motivation for sexual activity or a lack of desire to initiate
or participate in sexual activity must be accompanied by
clinically significant personal distress and must be present
for at least 6 months (2).
The newer DSM-5 merged two of the female sexual
dysfunction disorders into female sexual interest/arousal
disorder, eliminating HSDD and female sexual arousal dis-
order. However studies on treatment options for HSDD have
used DSM-IV-TR criteria. The ICD-11 available January 1,
2022, has a separate chapter entitled “Conditions Related to
Sexual Health,” which integrates some mental health and
behavioral disorders with some genitourinary disorders.
This chapter returns the diagnoses to parallel diagnoses for
men and women including HSDD and orgasmic dysfunction,
except for distinct clinical presentations (female sexual
arousal disorder and erectile dysfunction), and it also adds
pelvic pain/penetration disorder for both men and women.
Focus Vol. 19, No. 1, Winter 2021
CLINICAL SYNTHESIS
available as well as general diagnostic considerations for
psychiatrists. Given its importance in the understanding of
the available treatments for this disorder, the pathophysiol-
ogy behind HSDD is reviewed. The authors emphasize the
treatment of HSDD, including general treatment consid-
erations, treatment in the context of depression, and
psychotherapy and medications that have been approved
by the U.S. Food and Drug Administration.
Focus 2021; 19:39–45; doi: 10.1176/appi.focus.20200039
HSDD affects 10% of U.S. women (3). It is also associated
with depression and other negative emotional states (4, 5).
Therefore, it is imperative that psychiatrists are competent
to make this diagnosis and are aware of what treatment
options are available for their patients.
Among the subtypes of HSDD, the generalized acquired
form is the one that could benefit from pharmacological
treatment. Other subtypes, such as lifelong and situational,
are not discussed in this review.
DIAGNOSIS
To make the diagnosis, a sexual history and use of the De-
creased Sexual Desire Screener are recommended (Figure 1)
(6). The Decreased Sexual Desire Screener is quick and ef-
fective, and it requires no specific training to administer. It is
a validated instrument for confirming the diagnosis of gen-
eralized acquired HSDD. It consists of five “yes-no” ques-
tions. If the patient answers “yes” to the first four questions
and “no” to the items on question 5, they have generalized
acquired HSDD. Any items checked in question 5 may rep-
resent initiating events or modifiable factors for early in-
tervention. This instrument can also help initiate the
dialogue between patient and physician; moreover, it can
screen for potential etiologies of HSDD (Figure 1) and is in
the public domain, so it can be used freely in clinical
practice.
focus.psychiatryonline.org 39
TREATMENT OF HYPOACTIVE SEXUAL DESIRE DISORDER AMONG WOMEN
FIGURE 1. Decreased Sexual Desire Screenera
a
From Clayton et al. (6). Reprinted with permission from Elsevier.
DIAGNOSTIC CONSIDERATIONS FOR
PSYCHIATRISTS
It is important to obtain a full psychiatric and medical his-
tory to identify potential causes or contributing factors that
may need to be addressed first. Screening for depression is
particularly important, given its bidirectional relationship
with HSDD. Studies have shown that the risk of sexual
dysfunction is increased by 50%–70% among women with
depression. Inversely, women with sexual dysfunction have
a 130%–210% increased risk for depression (7, 8).
Sexual and/or physical trauma or psychological factors
can cause sexual dysfunction and likely require the addition
of psychotherapy to the treatment plan. Substance abuse or
dependence can also cause sexual dysfunction and should be
addressed separately and before interventions specific for
HSDD.
Certain antidepressants, such as selective serotonin reup-
take inhibitors (SSRIs), serotonin-norepinephrine reuptake
inhibitors (SNRIs), tricyclic antidepressants (TCAs), and
monoamine oxidase inhibitors (MAOIs), can cause sexual
dysfunction and can be managed with a dose reduction, switch
to a different antidepressant, or addition of an antidote. Some
antipsychotics, particularly risperidone or first-generation an-
tipsychotics, also cause sexual dysfunction; therefore, it might
be useful to obtain a prolactin level in these cases. Treatment
recommendations for depression and antidepressant-induced
sexual dysfunction are discussed in the following sections.
Providers should also screen for other sexual problems
such as arousal or orgasm dysfunction and sexual pain. If
present, these conditions might be contributing to or causing
the low sexual desire.
It is worth pointing out that numerous medical conditions
can cause or contribute to low sexual desire. Hypertension,
diabetes, metabolic syndrome, hypothyroidism, urinary in-
continence, neurological disorders, and malignancy have
all been associated with low sexual desire (9–11).
Several classes of medications have also been associated
with low sexual desire (Table 1). Broadly speaking, antihy-
pertensive medications, hormonal preparations, narcotics,
psychotropics, and chemotherapeutic agents have all been
40 focus.psychiatryonline.org
associated with decreased sexual desire (12). Because of
widespread use, it is important to inquire whether the pa-
tient is on an oral contraceptive pill (OCP). Checking sex
hormone binding globulin (SHBG) and testosterone levels
(total and free) might be helpful for this subset of patients,
given that OCPs can raise levels of SHBG, which increase
binding of testosterone, resulting in a decrease in free and
bioavailable testosterone. Although low testosterone is not
diagnostic of HSDD, treatment with testosterone may in-
crease sexual desire.
PATHOPHYSIOLOGY OF HSDD
HSDD is thought to be in part because of an imbalance
between excitatory and inhibitory pathways involved in
sexual response and behavior in the brain. Generally
speaking, dopamine, norepinephrine, testosterone, estro-
gen, and progesterone are excitatory, whereas serotonin,
prolactin, and opioids are inhibitory of sexual desire and
response. Pharmacological treatments for HSDD target
some of the neurotransmitters and hormones involved in
these pathways.
Other factors may also play a role, including psychoso-
cial variables (satisfaction with the relationship, self-image,
past sexual experiences among others), aging, menopause,
comorbid medical conditions, as well as substances and
medications (13, 14).
TREATMENT
General Considerations
We recommend first assessing the patient’s motivation for
treatment and their personal preferences. A variety of
treatment options are available for HSDD, including lifestyle
modifications and education, psychotherapy, sex therapy,
and pharmacotherapy. Treatment should be patient cen-
tered. Involving the patient’s partner should be considered.
It is also important to assess whether the level of distress is
significant enough to consider treatment options that carry
the risk of adverse effects.
Focus Vol. 19, No. 1, Winter 2021

It is important to screen for contributing psychological
factors. Examples include relationship strain, underlying
beliefs about sex, history of trauma, and body image issues.
In these cases, the appropriate psychotherapy modality to
treat these issues should be part of the treatment plan.
If there is concern for an underlying medical condition or
medications causing the symptoms, a referral to internal
medicine or the patient’s primary care provider should be
made. If pain with sexual activity is present, the patient
should be referred to gynecology for a targeted examination.
Treatment of HSDD in the Setting of Depression
If depression is present, it should be treated first because
untreated major depressive illness is associated with sexual
dysfunction. As mentioned earlier, SSRIs, SNRIs, and TCAs
can cause sexual dysfunction. For all four classes of antide-
pressants, sexual dysfunction is numerically but not statis-
tically significantly worse at higher doses (15). Antidepressants
that do not cause sexual dysfunction, or that cause it to a
lesser degree, are preferred (Table 2). These antidepres-
sants include bupropion and mirtazapine as well as two
drugs with serotonin reuptake inhibitor effects as part of
their mechanism of action: vortioxetine and vilazodone
(16). Vortioxetine recently had a change to its label that
states it causes significantly less sexual dysfunction than
SSRIs at rates similar to placebo at doses#10 mg for women
and at doses#15 mg for men. Should sexual dysfunction
occur at higher doses, decreasing the dose may improve
sexual function.
If augmentation with an antipsychotic is needed, aripi-
prazole and brexpiprazole are preferred options because
they have been shown to have a low rate of sexual side effects
compared with other antipsychotics (17, 18). If the patient is
already on one of these agents, assess whether it is con-
tributing to the sexual dysfunction. Reducing the dose or
switching to one of the antidepressants mentioned earlier
can be helpful (14, 19). Adjunctive treatment with bupropion
(20–22) or buspirone (23, 24) has also been shown to de-
crease sexual side effects. There is also evidence that ad-
junctive treatment with mirtazapine can decrease sexual
side effects from SSRIs (25).
If insomnia is present, it is recommended that the sleep
disturbance be treated independently and to monitor for
improvement of sexual symptoms. A study showed that
higher insomnia scores and shorter sleep duration were
associated with decreased sexual function (26). Flibanserin,
which is discussed later, can also potentially help with sleep
because of its sedating effects.
Psychotherapy
There are three types of psychological interventions that
have been found effective in treating or helping with female
sexual dysfunction and symptoms of HSDD.
Behavior therapy attempts to target sexual dysfunction
through a combination of communication skills training,
education, and sensate focus exercises (27).
Focus Vol. 19, No. 1, Winter 2021
PACHANO PESANTEZ ET AL.
TABLE 1. Medications associated with low sexual desire among
womena
Medication type Examples
Cardiac and Lipid-lowering medications, beta-blockers,
antihypertensive clonidine, digitalis, methyldopa,
spironolactone
Hormonal Androgen antagonists, danazol, GnRH
agonists and analogs, oral
contraceptives, tamoxifen
Opioids Any opioids used chronically, methadone
Psychotropic Antipsychotics, barbiturates,
benzodiazepines, lithium, MAOIs (oral),
phenytoin, SSRIs, SNRIs, TCAs
Other Aromatase inhibitors, chemotherapy,
histamine 2 receptor blockers,
nonsteroidal anti-inflammatory agents,
ketoconazole
a
GnRH, gonadotropin-releasing hormone; MAOIs, monoamine oxidase inhibitors;
SSRIs, selective serotonin reuptake inhibitors; SNRIs, serotonin-norepinephrine
reuptake inhibitors; TCAs, tricyclic antidepressants.
Cognitive-behavioral therapy (CBT) can be helpful by
challenging unrealistic beliefs contributing to low sexual
desire and by changing maladaptive behaviors that perpet-
uate HSDD. A review of psychological treatments for HSDD
found three studies in which CBT was effective for women
with HSDD compared with a waitlist control group (28).
Mindfulness-based CBT can help the patient increase
awareness of the present moment, minimizing cognitive
distractions during sexual activity and enhance awareness of
pleasurable sensations (29, 30). Two studies found positive
results with mindfulness training among women with HSDD
(28). Group mindfulness-based therapy has also been shown
to improve sexual desire among women (31, 32).
Resources might be limited depending on the commu-
nity; therefore, it might be beneficial to cultivate relation-
ships with providers who have expertise in these types of
psychotherapy.
Pharmacological Options
Flibanserin. Flibanserin (Addyi) was approved in 2015 by the
U.S. Food and Drug Administration (FDA) for treatment of
generalized acquired HSDD among premenopausal women.
Its mechanism of action is exerted through serotonin 1A
(5HT1A) receptor agonism and serotonin 2A (5HT2A) re-
ceptor antagonism. This process reduces serotonin in-
hibition of excitatory neurotransmitters and thus indirectly
increases release of dopamine and norepinephrine (33, 34).
Three randomized, double-blind, placebo-controlled tri-
als demonstrated that flibanserin was efficacious for HSDD
symptoms compared with placebo (35–37). All three studies
were conducted among premenopausal women, and all were
24 weeks long. Efficacy was measured with the Female
Sexual Function Index desire subscale (FSFI-D); Female
Sexual Distress Scale–Revised Item 13 (FSDS-R13), which
measures distress associated with sexual desire; and Satis-
fying Sexual Events (SSE), as determined by the woman. All
efficacy endpoints in the phase 3 studies demonstrated
focus.psychiatryonline.org 41
TREATMENT OF HYPOACTIVE SEXUAL DESIRE DISORDER AMONG WOMEN
TABLE 2. Antidepressant and antipsychotic medications with lower rates of sexual side effects or used for augmentation of SSRI- and
SNRI-induced sexual dysfunctiona
Treatment characteristic
Low rates of sexual side effects
Useful for augmentation of SSRI and SNRI
a
SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin-norepinephrine reuptake inhibitor.
b
Not approved by the U.S. Food and Drug Administration.
statistical significance in change from baseline to endpoint
over placebo. Relative to placebo, flibanserin had an effect
size of 0.29–0.44 (desire) and 0.24–0.44 (distress). Im-
provement was seen after 4 weeks of daily dosing. One study
found that 50 mg given at bedtime was efficacious (36);
however, another study did not find this dose to separate
from placebo (35). All studies found that 100-mg daily dosing
was effective in approximately 50% of women. Responders
found the effect to be clinically meaningful.
A 52-week open-label extension study found that fli-
banserin was safe and well tolerated. Sexual function im-
proved among participants who were initially nonremitters
and was maintained over time in remitters (38).
Even though flibanserin is not indicated for postmeno-
pausal women, evidence suggests that it is also effective
among this population (39). The recommended dose is 100 mg
given once daily at bedtime. When assessing for improvement,
one should inquire about changes in sexual desire, reduction
in distress related to sexual dysfunction, and satisfaction with
the treatment. If no improvement occurs after 8 weeks, one
should consider discontinuing this medication.
Flibanserin is safe to use concomitantly with SSRIs and
SNRIs. A small randomized, placebo-controlled trial dem-
onstrated no serious adverse effects and no instances of
suicidal ideation and behavior when combining flibanserin
100 mg daily with a stable SSRI or SNRI treatment regi-
men (40).
The most common adverse reactions (incidence$2%) in-
clude dizziness, somnolence, nausea, fatigue, insomnia, and
dry mouth. Hypotension and syncope have been reported, and
its package insert has a warning for these conditions (41).
Previously, concomitant use with alcohol was contra-
indicated and required a risk evaluation and mitigation
strategy (REMS) because of concerns for orthostatic hypo-
tension and syncope. Studies have demonstrated that it is
safe to use flibanserin with alcohol. Taking this medication 2,
4, and 6 hours after ethanol consumption did not increase
the incidence of hypotension, orthostatic hypotension, or
syncope compared with flibanserin or ethanol alone
(42–44). Thus, the REMS program was discontinued, and
the label was changed to recommend not using flibanserin
within 2 hours of alcohol consumption.
Flibanserin does not appear to prolong the corrected QT
interval (41). It is primarily metabolized by cytochrome
P450 3A4 (CYP3A4) and cytochrome P450 2C19 (CYP2C19);
therefore, one should review the patient’s medication list
for moderate and strong inhibitors or inducers of these
42 focus.psychiatryonline.org
Antidepressant-psychotropic Antipsychotic
Bupropion, mirtazapine, vilazodone, vortioxetine Aripiprazole, brexpiprazole
Bupropion,b buspirone,b flibanserin Aripiprazole
enzymes. The risk of severe hypotension is increased with
CYP3A4 inhibitors. Examples of strong CYP3A4 inhibitors
include clarithromycin, HIV protease inhibitors, ketocona-
zole, and grapefruit juice. Strong inducers of CYP3A4 in-
clude phenytoin, phenobarbital, rifampin, carbamazepine,
and St. John’s wort. Strong inhibitors of CYP2C19 include
fluoxetine, fluvoxamine, proton-pump inhibitors, antifungals,
and benzodiazepines.
Flibanserin can increase the concentration of drugs
transported by P-glycoprotein (P-gp). It is recommended to
increase monitoring of concentrations of drugs transported
by P-gp that have a narrow therapeutic index, such as digi-
talis and rapamycin.
The use of flibanserin is contraindicated in hepatic im-
pairment because there is a 4.5-fold increase to flibanserin
exposure in this population. Its use in pregnancy and
breastfeeding has not been studied; therefore, it is not
recommended.
Currently, this medication costs $99 per month without
insurance. However, discounts as low as $20 per month for
patients with commercial insurance can be found at https://
addyi.com/howtosave.
Bremelanotide. Bremelanotide (Vyleesi) was approved in
2019 by the FDA for treatment of generalized acquired
HSDD among premenopausal women.
Bremelanotide is a melanocortin 4 receptor (MC4R) ag-
onist. Neurons expressing the MC4R are present throughout
the central nervous system (45). The mechanism by which
bremelanotide improves HSDD is unknown, but it is thought
to increase excitation by enhancing dopamine and norepi-
nephrine activity.
The FSFI-D, item 13 of the Female Sexual Distress Scale-
Desire/Arousal/Orgasm (FSDS-DAO), and SSE were also
used in the phase 3 studies and demonstrated that breme-
lanotide is significantly more effective than placebo (46).
The combined effect size for the two phase 3 studies relative
to placebo was 0.39 for FSFI-D and 0.27 for FSDS-DAO item
13. The response rate for bremelanotide was 58.2% versus
35.6% for placebo in the integrated phase 3 data set. This
response was considered clinically meaningful by the study
participants. An extension study also showed that after
52 weeks, response to this medication was maintained (47).
The recommended dose is 1.75 mg administered sub-
cutaneously in the abdomen or thigh via an autoinjector, on
an as-needed basis. Patients should inject the medication at
least 45 minutes before a sexual encounter. It is not
Focus Vol. 19, No. 1, Winter 2021

recommended to use more than one dose within 24 hours, or
more than eight doses within 1 month.
As with flibanserin, one should inquire about changes in
sexual desire, reduction in distress related to sexual dys-
function, and satisfaction with the treatment to assess for
treatment response. If no improvement occurs after 8 weeks,
one should consider discontinuing this medication.
The most common adverse reactions (incidence$4%)
include nausea, flushing, headache, vomiting, and adverse
site reactions. Nausea is the most common adverse reaction.
In placebo-controlled trials, 40% of patients receiving bre-
melanotide reported nausea compared with 1% of patients
receiving placebo. Hyperpigmentation of the face, gingiva,
and breasts has also been reported (48).
Bremelanotide can cause transient increases in blood
pressure, and it is contraindicated in uncontrolled hyper-
tension. Providers should consider the patient’s cardiovas-
cular risk and ensure that blood pressure is well controlled.
Of note, bremelanotide can significantly decrease the
absorption of oral naltrexone, and its concomitant use is not
recommended. The use of intramuscular naltrexone can be
an alternative for this subset of patients.
This medication also has cost savings available online at
https://www.vyleesi.com/getting-started. With these dis-
counts, the current cost varies between $0 and $99 per 4-pack
of autoinjectors.
Testosterone. Although approved in Europe for treatment of
HSDD among women with surgical menopause, it is an off-
label treatment option in the United States. Studies on tes-
tosterone for HSDD have been largely conducted among
women who have undergone natural or surgical menopause.
Evidence is lacking for premenopausal women, and should a
woman become pregnant, fetal exposure may be associated
with significant negative consequences.
Three randomized, double-blind, placebo-controlled tri-
als have shown that a 300-mg/d transdermal testosterone
patch was superior to placebo in improving symptoms of
HSDD. Women who received this medication reported im-
provement in satisfying sexual events as well as a decrease
in levels of distress. Lower testosterone doses were not ef-
fective (49–52). This product was not approved in the
United States because of lack of information about long-term
consequences. These concerns have not been borne out in
use in other countries.
Transdermal use is recommended. Oral or intramuscular
preparations are not recommended because of high vari-
ability of absorption, which typically achieves supra-
physiologic levels and increases the risk of adverse effects.
Improvement of symptoms is expected within the first
3 months of treatment. If the patient does not experience
improvement in symptoms after 3–6 months, consider dis-
continuing treatment (53).
The most common side effects are acne, application site
reactions, breast pain, headache, and hirsutism. In several
Focus Vol. 19, No. 1, Winter 2021
PACHANO PESANTEZ ET AL.
studies, liver function, lipid profile, hematologic tests, and
clotting measures remained essentially unchanged (49–52).
Baseline and follow-up testosterone levels should be
obtained. Levels should be maintained within normal
ranges. Short-term safety data are reassuring when testos-
terone levels are maintained within normal levels (54).
However, long-term data are limited to observational stud-
ies, including safety data with regard to breast cancer and
cardiovascular events (55).
Testosterone formulations for women are not widely
available. Most clinicians will have to use topical formula-
tions for men but at a much lower dose, generally one-
seventh to one-tenth of approved doses for men to avoid
virilization. Compounded formulations are another option.
CONCLUSIONS
HSDD affects 10% of U.S. women. Assessment should in-
clude comorbid medical, psychiatric, and sexual disorders
and their associated treatments, which may inform man-
agement. Addressing modifiable factors and utilizing tar-
geted interventions will provide optimal care to women with
HSDD.
AUTHOR AND ARTICLE INFORMATION
Department of Psychiatry and Neurobehavioral Sciences, University of
Virginia, Charlottesville. Send correspondence to Dr. Clayton (ahc8v@
virginia.edu).
The authors thank Stephen Furry for assistance with formatting and
submitting the article.
Dr. Clayton has received grants from Janssen, Relmada Therapeutics,
and Sage Therapeutics. Dr. Clayton has also received advisory board or
consultant fees from Acadia, Alkermes, Allergan, Fabre-Kramer, Ovoca
Bio, PureTech Health, S1 Biopharma, Sage Therapeutics, Takeda/
Lundbeck, and WCG MedAvante-ProPhase. In addition, Dr. Clayton has
received royalties from Ballantine Books/Random House and Guilford
Press and holds the copyright of the Changes in Sexual Functioning
Questionnaire. Finally, Dr. Clayton owns shares or restricted stock units
in Euthymics, Mediflix, and S1 Biopharma. Dr. Pachano Pesantez reports
no financial relationships with commercial interests.
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focus.psychiatryonline.org 45
CLINICAL SYNTHESIS
Innovations in Psychopharmacology Education in U.S.
Psychiatric Residency Programs
Jeffrey Rakofsky, M.D.
Medications available to treat psychiatric illnesses continue to
increase, in conjunction with a shifting of outpatient psychiatric
practice from psychotherapy toward medication management.
To be successful in this climate, a psychiatrist needs to select the
appropriate pharmacologic option(s) for their patient, drawing
from old and new psychotropics while accounting for variables
such as a patient’s comorbid medical conditions and
potential drug-drug interactions. In the absence of any national
psychopharmacology training guidelines, these skills are taught
to varying degrees in American psychiatric residency training
Since the introduction of lithium in 1949, the number of
medications available to treat psychiatric illnesses has
steadily increased, providing modern clinicians a sizeable
armamentarium of medications with diverse formulations,
mechanisms of action, and targets. Concurrently, over the
past 3 decades, the practice of outpatient psychiatry has
moved away from psychotherapy toward medication man-
agement (1, 2) and more complex psychopharmacologic
regimens (3). To be successful in this climate, a psychiatrist
must be able to select the appropriate pharmacologic
option(s) for the patient, drawing from a long list of old and
new psychotropics while taking into account variables such
as a patient’s comorbid medical conditions and potential
drug-drug interactions. The psychiatrist must know how to
prescribe the medicine, striking a balance between tolera-
bility and efficacy. Finally, he or she must know how to re-
spond to adverse events, nonadherence, or breakthrough
symptoms that may develop with time.
These skills are likely taught to varying degrees in
American psychiatric residency training programs. A na-
tional survey study of postgraduate year (PGY)-3 and PGY-4
psychiatry residents revealed that many of the respondents
failed to initiate mood stabilizers, including lithium, val-
proate, carbamazepine, and lamotrigine, for their patients
with bipolar disorder in their most recent training year (4).
The lack of consistency among programs may be due to the
absence of specific, detailed program requirements for psy-
chopharmacology training established by the Accreditation
46 focus.psychiatryonline.org
programs. The past 20 years have seen an increase in innovations
in the areas of psychopharmacology curricula topics, teaching
strategies, and assessments of psychopharmacology knowledge
and skills. Psychiatric training programs can benefit from and
build on these innovations, ensuring that all physicians graduating
from a psychiatric residency program meet psychopharmacology-
based learning objectives and that their learning can be
measured in a valid and reliable way.
Focus 2021; 19:46–49; doi: 10.1176/appi.focus.20200037
Council for Graduate Medical Education (ACGME) (5).
Additionally, the inconsistency may be due to the lack of
faculty with psychopharmacologic expertise or of specialty
clinics for illnesses such as treatment-resistant schizophre-
nia or bipolar disorder at various residency programs across
the country. In a survey of U.S. psychiatry residency pro-
gram directors, 34% reported a need to enhance their pro-
gram’s overall psychopharmacology curriculum (6). With
the growing need to provide robust and effective psycho-
pharmacology training, psychiatric educators over the past
20 years have developed and published several innovations
in the form of pedagogical practices and assessment strate-
gies. I review these innovations next and then offer future
considerations to help program directors and educators
strengthen psychopharmacology training for the psychia-
trists of the next generation.
PEDAGOGY
The pedagogical approaches to teaching psychopharmacol-
ogy consider which topics to teach (content) and how to
teach them (methods). Over the past 20 years, several psy-
chopharmacology publications have described innovations
in both areas. Regarding content, educators have reported
their experiences teaching a wide range of topics, including
the psychodynamics of psychopharmacology, which ex-
plores how the psychosocial factors in the doctor-patient
relationship influence medication effectiveness (7); biological
Focus Vol. 19, No. 1, Winter 2021

psychiatry, which combines neurosciences and psychophar-
macology (8, 9); the psychopharmacological treatment of
various psychiatric illnesses (10, 11) and their established
treatment algorithms (9); the evaluation of psychopharma-
cology clinical trials (9, 12); the nuances around prescribing
clozapine and managing side effects (13); the assessment and
management of medication nonadherence (14); and the in-
formed consent process for initiating new medications (15).
The majority of these topics are contained within the
American Society of Clinical Psychopharmacology (ASCP)
Model Psychopharmacology Curriculum, which consists of
a comprehensive collection of lectures on various topics
related to psychopharmacology. This curriculum originated
in 1984 and has been updated every 2 years (16). The most
recent list of included lectures can be found on the ASCP
website (https://ascpp.org/resources/educational-resource/
ascp-model-psychopharmacology-curriculum-seventh-edition).
In addition to many of the topics listed earlier, the curriculum
also includes lectures on the art of psychopharmacology,
cross-cultural psychiatry, combining psychotropics with
psychotherapy, ethical issues in psychopharmacology, and
industry interactions (17).
In regard to the methods for teaching these topics, vari-
ous strategies have been reported that incorporate principles
of adult learning, including the need for learners to be active
and self-directed (8). Most of the publications reported
earlier describe multimodal educational efforts that usually
have some lecture or didactic component as a starting point.
For example, in addition to the lectures, the ASCP Model
Psychopharmacology Curriculum and University of Mas-
sachusetts biological psychiatry seminars include additional
elements such as journal clubs, problem-based learning,
games, and case conferences (8, 10, 11). When teaching res-
idents the components of the informed consent process for
initiating new medicines, Kavanagh et al. (15) used a com-
bination of role-playing exercises and group discussion.
Weiden and Rao (14) also used role-playing activities along
with case vignettes and lectures to teach residents how to
assess and manage medication nonadherence. To train res-
idents in the use of clozapine, Freudenreich et al. (13)
worked with PGY-2 residents in a clozapine specialty clinic
over 6 weeks. The residents received clozapine specific di-
dactics in a small group session at the beginning of every
clinic and then immediate supervision and feedback after
each patient encounter. Finally, Mohr et al. (12) developed a
23-item appraisal instrument to guide residents through a
systematic assessment of psychopharmacologic clinical trials.
ASSESSMENT
Assessment is a vital component of psychopharmacology
training because it provides essential feedback to stake-
holders (i.e., residents, faculty, program directors, state li-
censing boards, specialty certification boards). Across most
residency programs, assessment in psychopharmacology
knowledge and skills occurs via the Psychiatry Residency In
Focus Vol. 19, No. 1, Winter 2021
RAKOFSKY
Training Exam (PRITE) and the ACGME Psychiatry Mile-
stones assessment, both of which present limitations (18).
Assessment can be divided into two broad categories: for-
mative and summative. Formative assessments provide the
student and teacher with data about the student’s progress
and can help the student become more self-directed and
accelerate their learning (19). Summative assessments pro-
vide an overall evaluation of the student’s mastery of the
material at the completion of the course (20). Both types of
assessment are fundamental to psychiatric training and have
been developed for use in psychiatric residency programs.
Among formative assessments, Young et al.’s (21)
Psychopharmacotherapy-Structured Clinical Observation
(P-SCO) instrument stands out. This 27-item checklist in-
cludes essential tasks to be completed during a psychiatric
medication management visit. Faculty observe residents
during clinic visits and indicate whether and to what degree
residents complete the 27 tasks. The faculty member then
provides specific feedback to the resident. Compared with
global assessments of resident performance, the P-SCO as-
sessments provided residents 3.3 times more patient-care
specific comments, particularly for corrective and reinforc-
ing comments. A follow-up study provided additional val-
idity evidence with respect to the tool’s internal structure
and its correlation with resident experience (22). Another
formative assessment includes measuring residents’ confi-
dence levels initiating and managing the side effects of var-
ious psychotropics. Rakofsky et al. (23) showed that
confidence prescribing medicines from particular classes of
psychotropics varied with experience prescribing those
medicines over a 12-month academic year. By eliciting resi-
dents’ confidence levels early in the academic year, educa-
tors can tailor the training experience to boost those levels
where it is most needed.
In the category of summative assessments, a few of the
curricula described earlier include pre- and postassessments
to ensure that residents mastered the content (13, 24). A
more recent publication describes the creation of a virtual
standardized patient-based assessment tool to evaluate
psychiatric residents’ psychopharmacology proficiency in
the treatment of major depressive disorder (18). The tool is
an online simulator that replicates the outpatient psychiatric
clinic experience. The virtual patient reports symptoms of a
treatment-resistant form of depression, and the resident is
required to use various antidepressants until the patient fi-
nally remits. The resident earns points for correct responses
to questions asked by the virtual patient about topics such as
dosing, titration decisions, and side effects.
FUTURE CONSIDERATIONS
The innovations in pedagogy and assessment reported ear-
lier address a variety of topics in psychopharmacology,
learning styles, and assessment types. However, opportuni-
ties are available to add to these innovations and continue
improving psychopharmacology education. Integrating the
focus.psychiatryonline.org 47
INNOVATIONS IN PSYCHOPHARMACOLOGY EDUCATION IN U.S. PSYCHIATRIC RESIDENCY PROGRAMS
neuroscience-based nomenclature (NbN) into residency
education may be one such innovation. The NbN was de-
veloped in 2008 by a task force of scientific organizations
including the American, Asian, European, and International
Colleges of Neuropsychopharmacology and the Inter-
national Union of Basic and Clinical Pharmacology (25). Its
goal is to reclassify psychiatric medicines on the basis of
their neuronal targets rather than their clinical indications.
The task force has developed a free app, which is updated
every 2 years, that provides detailed information about the
pharmacology and mode of action of psychiatric medicines.
Residency lectures and communications between attending
physicians and residents can incorporate these new classi-
fications, helping residents learn the new terminology and
improve their understanding of how these medications
work.
Another opportunity stems from the lack of specific, de-
tailed psychopharmacology program requirements estab-
lished by the ACGME. Residents’ psychopharmacology
education may benefit from a national expert consensus–
defined list of psychopharmacology learning objectives. The
ASCP Model Psychopharmacology Curriculum is compre-
hensive and likely addresses the learning objectives that
would be included; however, one of the limitations to the
curriculum has been educators’ reluctance to replace their
own lecture material with that provided by the ASCP (24).
Developing only a defined set of learning objectives would
provide residency programs a guide for the topics they
should teach and the flexibility to teach them in the manner
they choose. Psychiatric educators in Europe have proposed
such a list, providing topics ranging from basic principles of
pharmacology to the implementation and application of
these medications in the treatment of various psychiatric
illnesses. They also provide the number of hours that should
be dedicated to teaching those topics (26).
Building on Freudenreich et al.’s (13) example, residency
programs can identify psychiatric specialty clinics within
their institution (e.g., clozapine, women’s mental health,
bipolar disorder, treatment-resistant depression) and seek
opportunities for their residents to work in those settings.
Incorporating more digital technology—such as audience
response systems, apps, video telecommunications to in-
clude patients or expert psychopharmacologists, and other
tools—will ensure that presentations are multimodal and
interactive, consistent with adult learning theories.
In the realm of assessment, developing virtual stan-
dardized patient simulators focusing on the treatment of
psychiatric illnesses besides major depressive disorder,
including bipolar disorder, schizophrenia, and obsessive-
compulsive disorder, would provide additional opportunities
to evaluate a resident’s psychopharmacologic proficiency.
Developing a national exam for residents that focuses ex-
clusively on psychopharmacology knowledge (similar to the
ASCP Exam in Advanced Clinical Psychopharmacology)
may be an opportunity to widen the scope of psychophar-
macology knowledge assessment beyond that of the PRITE.
48 focus.psychiatryonline.org
Finally, more research in psychopharmacology education is
needed. Studies that identify the extent and depth of U.S. res-
idents’ psychopharmacology knowledge will help determine
how well American residency programs are preparing their
graduates. Scores on the PRITE psychopharmacology ques-
tions can shed some light on this question. Research on the
most effective methods for teaching psychopharmacology is
also greatly needed to help educators select the optimal ap-
proach for training residents, taking into account PGY level and
adult learning theories.
CONCLUSIONS
The increased role of psychopharmacology in the practice of
psychiatry is leading psychiatric educators to shift their fo-
cus to ensure that psychiatric residents can competently
prescribe and manage the side effects of a diverse range of
psychotropic medications. Fortunately, the past 20 years
have seen an increase in the number of publications
reporting innovations in the areas of psychopharmacology
curricula topics, teaching strategies, and assessments of
psychopharmacology knowledge and skills. Psychiatric
training programs can benefit from and build on these in-
novations, ensuring that all physicians graduating from a
psychiatric residency program meet psychopharmacology-
based learning objectives and that their learning can be
measured in valid and reliable ways.
AUTHOR AND ARTICLE INFORMATION
Department of Psychiatry and Behavioral Sciences, Emory University
School of Medicine, Atlanta. Send correspondence to Dr. Rakofsky
(jrakofs@emory.edu).
Dr. Rakofsky has received speaking honoraria from SMI Clinical Adviser
and has received research funding from Compass, Otsuka, the American
Board of Psychiatry and Neurology, and the Association of Directors for
Medical Student Education.
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focus.psychiatryonline.org 49
ASK THE EXPERT
Moving on With Monoamine Oxidase Inhibitors
J. Alexander Bodkin, M.D., and Boadie W. Dunlop, M.D.
For patients whose depression has not been responsive to
selective serotonin reuptake inhibitor or serotonin-norepinephrine
inhibitor treatment and for whom treatment with a mono-
amine oxidase inhibitor seems warranted, how best can the
drug-free interval required by the Food and Drug Adminis-
tration for such a transition be managed?
Estimates indicate that 15%220% of patients presenting for
treatment of major depression require monoamine oxidase
inhibitor (MAOI) treatment for optimal response, but the
rate of prescription of MAOIs in the United States in 2005
was less than 0.1% (1). A 1999 survey found that 40% of
psychiatrists had not prescribed an MAOI in the previous
3 years, and only 2% of psychiatrists prescribed them fre-
quently (2); these numbers have certainly worsened since
then, as older psychiatrists have retired. These low rates are
even more remarkable considering the easing of the dietary
restrictions to be followed while on MAOI therapy (3). This
problematic reluctance on the part of patients and providers
clearly needs to be addressed. In our experience, this re-
luctance stems in part from fears of patients worsening in
the period between discontinuation of current antidepres-
sants and initiation of the MAOI. However, once the decision
to try an MAOI is made, the transition is rarely difficult and
need not require any interval off treatment.
MAOIs are among the oldest medications in the psychi-
atric pharmacopeia, with demonstrated efficacy in unipolar
and bipolar depression, social anxiety disorder, posttrau-
matic stress disorder, and panic disorder. The four MAOIs
approved in the United States for depression are phenelzine,
tranylcypromine, isocarboxazid, and transdermal selegiline
(4), which all irreversibly inhibit monoamine oxidase (MAO).
Phenelzine, isocarboxazid, and tranylcypromine inhibit both
MAOA (which degrades serotonin, norepinephrine, and do-
pamine) and MAOB (which degrades dopamine) throughout
their dose ranges. Transdermal selegiline is selective for MAOB
at low doses and inhibits MAOA to a therapeutic degree at a
dosage of at least 6 mg every 24 hours.
The two primary safety concerns with MAOI treatment
are a hypertensive crisis reaction and serotonin syndrome.
Hypertensive crises can arise from the pharmacodynamic
interaction of MAOIs with sympathomimetic drugs or ex-
cessive dietary tyramine intake. Serotonin syndrome occurs
when medications that enhance serotonin availability (pri-
marily the serotonin reuptake inhibitors [SSRIs] and serotonin-
norepinephrine reuptake inhibitors [SNRIs]) are taken when
MAO activity is inhibited. Because of these risks, MAOIs are
50 focus.psychiatryonline.org
not typically considered as a treatment option for patients
until several other treatments have failed. However, this
scenario presents the complications of transitioning to an
MAOI from an existing regimen, which may be complex and
include medications contraindicated with MAOIs.
It is important to briefly consider why such a switch may
make sense in a given case. Uptake-inhibiting antidepres-
sants are all similar in their primary mechanism of action,
whereas MAOIs have a primary mechanism of action that is
completely different from that of antidepressants that are in
wide general use. Rather than induce prolonged accumula-
tion of serotonin and norepinephrine in the intrasynaptic
clefts throughout the brain, as do SSRIs, SNRIs, and tricyclic
antidepressants, MAOIs, by inhibiting MAO, have the effect
of increasing the stores of presynaptic monoamines available
for release into the synapse as regulated by processes such as
feedback inhibition. These presynaptic stores include not
only serotonin and norepinephrine but also the behaviorally
salient monoamine dopamine, a deficit of which may have an
important role in persistent depressive symptoms such as
apathy, psychomotor retardation, and anhedonia (5).
Rather than waiting for numerous medication failures
before beginning an MAOI, an assessment of the patient’s
symptom picture can warrant earlier initiation of this class
of medication (6). MAOIs have been demonstrated to have
superior efficacy to tricyclic antidepressants for depression
characterized by atypical features (7, 8). Atypical depression
includes mood responsivity to positive events at a level of at
least 50% along with at least two of the following: an ex-
cessive need for sleep, hyperphagia, prominent lethargy or
anergia, and a long-standing pattern of oversensitivity to
personal rejection. A variant of atypical features that does
not focus on rejection sensitivity but emphasizes the reverse
neurovegetative symptoms of hypersomnia, hyperphagia,
anergia and loss of motivation also shows good response to
MAOIs (9).
When a prescriber decides to move a patient who is on
a serotonin reuptake inhibitor to an MAOI, the question
becomes how to make the transition safely, balancing the
competing risks of potential drug interactions against the
risk of a period without antidepressant coverage and clini-
cal deterioration. Approaching this problem is made more
complex by the highly restrictive guidance on the MAOI
product labels approved by the Food and Drug Administration
(FDA), compared with the more flexible recommendations of
experts with deep clinical experience with MAOIs.
Focus Vol. 19, No. 1, Winter 2021

The FDA labels for the marketed MAOIs state that sym-
pathomimetic drugs, such as stimulants, and the 5-HT1a
receptor antagonist buspirone are contraindicated because
of hypertensive risks (10–13). Tryptophan supplements,
certain opiates, and dextromethorphan are contraindicated
because of the risk of serotonin syndrome. Antidepressants
as a class, and regardless of mechanism of action, are listed
as contraindicated because of serotonin syndrome risk, and
some are contraindicated for hypertensive risk. This re-
striction includes drugs that have no direct action on serotonin
as well as agents that act by antagonizing serotonin receptors
but not transporters, such as mirtazapine. The restriction also
extends to carbamazepine and oxcarbazepine because of their
shared dibenzoazepine structure with tricyclics. Lithium is
listed as “use with cautions” on the tranylcypromine label, a
dubious warning that is appropriately absent from the label-
ing of other psychotropics. Such broad restrictions make it
difficult to transition a patient to an MAOI from an existing
antidepressant regimen. In contrast, the first author has
used bupropion, mirtazapine, and trazodone in combination
with MAOIs for many years with no adverse consequences,
as have many members of the international MAOI experts
group (maoi-expert-group@googlegroups.com).
Other medications less commonly considered to carry
risk with MAOIs include blood-pressure-lowering agents,
which may act synergistically with the hypotensive side ef-
fect sometimes observed on initiating an MAOI and carry
warnings on the tranylcypromine and isocarboxazid labels.
Thus, particular attention should be paid to such drugs used
in psychiatry, including alpha-1 antagonists such as prazosin
and certain antipsychotics, alpha-2 agonists such as cloni-
dine and guanfacine, and beta blockers, such as propranolol.
The tranylcypromine label also asserts that nonselective
histamine type 1 receptor antagonists, such as diphenhy-
dramine, are contraindicated because of increased anticho-
linergic effects, and triptans, such as sumatriptan, which
agonize serotonin type 1B and 1D receptors, are contra-
indicated because of the risk for serotonin syndrome (12).
These additional contraindications on the tranylcypromine
label are not well supported by the literature and not present
on the labels of transdermal selegiline or phenelzine.
Regarding the duration of the drug-free interval, the FDA
labels state that contraindicated medications, including an-
tidepressants, should be discontinued for at least four to five
half-lives of the parent drug, or any active metabolites, be-
fore initiating an MAOI. For most antidepressants this
means about 5–7 days, although 2–3 weeks are required for
vortioxetine and 5 weeks for fluoxetine. Antidepressants
with most rapid clearance are venlafaxine (3 days) and
desvenlafaxine (2 days).
The Transition
Our recommended strategy for the shift from a failed
course of treatment with an SSRI or an SNRI to an MAOI is
to introduce an antidepressant with no dangerous MAOI
Focus Vol. 19, No. 1, Winter 2021
BODKIN AND DUNLOP
interaction while the failed medication is being tapered. Safe
antidepressant options include mirtazapine (14), trazodone
(15), and tricyclics other than clomipramine or imipramine
(16); nortriptyline is one we often use. If this step brings the
patient to recovery, no further measures need be taken, and
an MAOI will not be required. However, if after an adequate
trial of the added antidepressant, or some combination of the
permissible agents, there has not been a satisfactory clinical
response, an MAOI can be initiated. The dose of the MAOI
can be increased following the usual dosing strategy con-
currently with the tapering of the safe medications. Notably,
if there has been a partial but worthwhile response to the
transitional medications, they can be retained throughout
MAOI therapy. With a tricyclic such as nortriptyline, this is
particularly sensible because there is greater safety in adding
an MAOI to an established tricyclic antidepressant than vice
versa.
Notably, if in addition to an SSRI or an SNRI the patient is
on one or more antidepressant adjuncts, such as aripipra-
zole, quetiapine, triiodothyronine, gabapentin, pregabalin,
lamotrigine, or a benzodiazepine, these agents can be con-
tinued unchanged. Leaving them in place may make the
period preceding MAOI initiation less uncomfortable. In
contrast, the old practice of prescribing a “rescue” rapid-
acting blood-pressure-lowering agent (e.g., nifedipine) to be
taken by the patient in the case of symptoms of a hyper-
tensive reaction is no longer recommended because of the
established serious risks of brain, cardiac, and renal hypo-
perfusion stemming from an acute blood pressure reduction.
A point worth making is that instead of an unpleasant
discontinuation syndrome, we have occasionally observed
that some patients experience a period of mild elation on
discontinuation of a monoamine reuptake inhibitor such as
paroxetine or duloxetine. This experience rarely lasts more
than 2 weeks before mood sinks back into depression. So, in
cases in which the antidepressants that are safe to combine
with MAOIs have previously been tried and failed, such that
the bridging strategy is not possible, or if a patient prefers to
move straight from the unsatisfactory current regimen to a
trial of an MAOI, they can be advised that it is possible their
mood may brighten for a short time after coming off the
reuptake inhibitor. If instead they slump in mood, then a
brief course of treatment with a benzodiazepine, gabapentin,
or low-dose quetiapine may make the washout period more
tolerable.
A final precaution: Tapering off SSRIs and SNRIs, par-
ticularly paroxetine or venlafaxine, even gradually, may be
associated with such acute dysphoria that the patient is
strongly inclined to just go back on the unsatisfactory agent
rather than pursue the well-being that MAOIs offer. In such
cases, it is critical to make clear to the patient that this is not
a recurrence of depressive illness but an acute discontinu-
ation syndrome. Therefore, returning to the agent being
discontinued would not relieve depressive illness, which
would not have acute onset but rather would have slowly
crept up with the passage of time off effective treatment.
focus.psychiatryonline.org 51
MOVING ON WITH MONOAMINE OXIDASE INHIBITORS
In these cases, a slower SSRI or SNRI taper, along with the
addition of a safe transitional medication, is the best ap-
proach to enable the patient to reach the potential benefit of
an MAOI trial.
AUTHOR AND ARTICLE INFORMATION
Department of Psychiatry, McLean Hospital, Harvard Medical School,
Belmont (Bodkin); Department of Psychiatry and Behavioral Sciences,
Emory University School of Medicine, Atlanta (Dunlop). Send corre-
spondence to Dr. Bodkin (abodkin@mclean.harvard.edu).
Dr. Bodkin has received research support from Alkermes and Otsuka
and has served as a consultant to both firms. Dr. Dunlop has received
research support from Acadia, Aptinyx, Compass, National Institute of
Mental Health, Sage, and Takeda and has served as a consultant to
Greenwich Biosciences, Myriad Neuroscience, Otsuka, Sage, and
Sophren Therapeutics.
Focus 2021; 19:50–52; doi: 10.1176/appi.focus.20200046
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1. Frampton JE, Plosker GL: Selegiline transdermal system: in the treatment
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3. Gardner DM, Shulman KI, Walker SE, et al: The making of a user
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5. Dunlop BW, Nemeroff CB: The role of dopamine in the patho-
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6. Thase ME, Trivedi MH, Rush AJ: MAOIs in the contemporary treat-
ment of depression. Neuropsychopharmacology 1995; 12:185–219
7. Quitkin FM, Stewart JW, McGrath PJ, et al: Phenelzine versus
imipramine in the treatment of probable atypical depression:
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defining syndrome boundaries of selective MAOI responders. Am J
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panic attacks, and response to imipramine and phenelzine: a rep-
lication. Arch Gen Psychiatry 1990; 47:935–941
9. Thase ME: Atypical depression: useful concept, but it’s time to
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sert]. Washington, DC, US Food and Drug Administration, 2018.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid5ac387aa0-
3f04-4865-a913-db6ed6f4fdc5. Accessed Oct 9, 2020
11. Parke-Davis Division, Pfizer Inc: Nardil (phenelzine) [package in-
sert]. Washington, DC, US Food and Drug Administration, 2008.
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37d4-4355-8a6d-a2c643bce6fa. Accessed Oct 9, 2020
12. Concordia Pharmaceuticals: Parnate (tranylcypromine) [package
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fdb8-4862-89c5-ecdd700398a3. Accessed Oct 9, 2020
14. Gillman PK: A systematic review of the serotonergic effects of
mirtazapine in humans: implications for its dual action status. Hum
Psychopharmacol 2006; 21:117–125
15. Nierenberg AA, Keck PE Jr: Management of monoamine oxidase
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Focus Vol. 19, No. 1, Winter 2021

Ethical Issues in Psychopharmacology
Nataly S. Beck, M.D., Daniel S. J. Kim, M.D., Laura B. Dunn, M.D.
Psychopharmacology is the scientific study of the effect of
medications on the mind and behavior. Many ethical issues
arise within the broader realm of psychopharmacology, in-
cluding the fair allocation of resources or the weighing of
risks versus benefits in the prescribing of medications. The
ethical psychiatric practitioner has the responsibility to
know and continue to learn the latest empirical findings on
psychopharmacologic and psychosocial treatments, in-
cluding their indications, adverse effects, and contraindica-
tions (1–3).
In this article, ethical principles in psychopharmacology
will be addressed. Ethical principles include the following:
Respect for persons: regard for an individual’s worth and
dignity
Autonomy: self-governance
Beneficence: the responsibility to act in a way that seeks to
provide the greatest benefit
Fidelity: faithfulness to the interests of the patient
Nonmaleficence: the commitment to do no harm
Veracity: the duty of truth and honesty
Justice: the act of fair treatment, without prejudice
Privacy: protection of patients’ personal information
Integrity: honorable conduct within the profession
All psychiatrists commonly confront ethical dilemmas when
considering psychopharmacologic indications, benefits, and
risks, as well as those of alternative management strategies.
To the experienced clinician, balancing these factors may
come to feel like second nature, particularly when the
treatment context includes a solid rapport with the patient.
Furthermore, patients with intact cognition, insight, and
judgment are typically able to engage meaningfully in shared
decision making, which then unfolds naturally over the
course of treatment. However, in many other cases, psy-
chopharmacologic management raises a host of ethical is-
sues with no easy or optimal solutions. Three cases,
presented below, illustrate a few of these challenges.
Case 1
TL is a 58-year-old woman with a history of bipolar disorder,
attention-deficit hyperactivity disorder, and anxiety. After
Focus Vol. 19, No. 1, Winter 2021
ETHICS COMMENTARY
moving from another state, she presented to find a new
psychiatric provider. Upon interview of the patient and re-
view of her medications, TL’s new psychiatrist saw that she
had been prescribed divalproex sodium, alprazolam, and
modafinil by her previous psychiatrist. The dosing patterns
appeared unconventional, and the interview revealed that at
least some of the dosing variation was patient driven (e.g.,
dosing divalproex sodium daily with an additional dose ev-
ery 3 days, dosing modafinil and alprazolam in very small
doses multiple times a day, and daily variability in the doses
taken of these two medications).
1.1 What is the most appropriate initial step for the psychiatrist
in this case? (More than one response may be appropriate.)
A. Elicit more detail from TL about her perspectives on
her medications.
B. Discontinue the alprazolam and modafinil.
C. Ask TL to describe in more detail the benefits of each
medication and for what specific symptoms they are
being used.
D. Inquire about any side effects TL has experienced.
E. Discuss overall goals for treating anxiety and lack of
energy besides the controlled substances of alprazo-
lam and modafinil.
F. Check the controlled substance monitoring database
in TL’s current state and also her previous state of
residence, if possible.
G. Contact TL’s previous outpatient psychiatrist to dis-
cuss the details of her case.
H. All of the above.
TL described that, after numerous medication trials over the
years, alprazolam, modafinil, and divalproex sodium are the
only medications that have helped her psychiatric symptoms
reach stability. In addition, she stated that she is very sen-
sitive to medications and thus responds to very small doses
of medications, especially when dosed throughout the day.
She stated that she used to be on much higher doses of
alprazolam and modafinil in the past but has been able to
wean herself off these higher doses.
TL’s care was also complicated by having insurance that
restricts medications to certain formulary-approved medi-
cations. She also must pay a large copay for her office visits.
focus.psychiatryonline.org 53
ETHICS COMMENTARY
1.2 What is the most appropriate next step for the
psychiatrist?
A. Find alternatives that are more affordable, such as
using divalproex sodium delayed release, instead of
the extended-release formulation, which is more
expensive.
B. Recommend that the patient conduct a search of
prescription savings programs to find medications at a
lower cost, and even do the search together.
C. Manage medication changes over the phone or
through electronic messages to help decrease the cost
and frequency of office visits.
D. Fill out prior authorization forms for TL’s medications.
After a patient-centered discussion, TL and the psychiatrist
agreed to gradually try other medications instead of the
alprazolam and modafinil, such as cross-tapering from
alprazolam onto clonazepam for decreased risk for de-
pendence and using trazodone to help with sleep. In addi-
tion, TL agreed to try to take more regular doses of
medications instead of changing them as needed. Although
these changes were done slowly and one at a time, the
changes resulted in TL having substantially increased anxi-
ety and mood lability. The psychiatrist then cross-tapered
the medications back to her previous medications, with ad-
justment of alprazolam and modafinil to the lowest possible
doses that helped TL’s symptoms.
1.3 What were the ethical principles involved in the agree-
ment between the psychiatrist and TL that she use
alprazolam and modafinil and use the medications in her
previous unusual dosing patterns?
A. Integrity and privacy
B. Justice and fidelity
C. Respect for persons and veracity
D. Autonomy and beneficence
Case 2
Mr. R was a 71-year-old married Caucasian man who was
referred by his primary care physician to an outpatient ge-
riatric psychiatry clinic for evaluation and management of
agitation. The referral stated that the patient was diagnosed
as having Alzheimer’s disease 6 years ago and that the pa-
tient’s agitation started approximately 2 to 3 years ago. Al-
though his wife had received caregiver education and
support through the local Alzheimer’s Association chapter
with some improvement in her ability to redirect the patient,
she was nonetheless experiencing additional caregiver
burnout, despite additional support from their children liv-
ing in the community. At the time of his initial visit to geri-
atric psychiatry, the patient’s cognition was obviously
impaired. He was minimally responsive to questions, be-
came irritable when asked basic questions, and was unable to
tolerate a cognitive assessment. The history was obtained
from the patient’s wife, Mrs. R.
54 focus.psychiatryonline.org
At the initial geriatric psychiatry visit, Mrs. R reported
that the agitation had been worsening over the past several
months. The behaviors consisted of resisting care, restless-
ness and purposeless behaviors, screaming, and occasional
physical aggressiveness. Upon detailed questioning, it be-
came apparent that his behavioral issues were exacerbated
over the past year by worsening nonfluent aphasia and in-
creased functional limitations, including bowel and bladder
incontinence requiring more invasive caregiving. Although
the agitation also appeared to be associated with paranoia
toward caregivers, Mrs. R—who was the primary caregiver
and designated power of attorney—adamantly declined
consideration of psychotropic medications, including cho-
linesterase inhibitors, instead querying regarding comple-
mentary or alternative interventions.
2.1 What is the most appropriate next step in the manage-
ment of Mr. R’s agitation? (More than one answer may be
appropriate.)
A. Attempt to persuade Mrs. R to agree to a trial of
risperidone.
B. Ask Mrs. R to carefully observe and document the
patient’s behaviors to identify potential triggers and
unmet physical or emotional needs.
C. Prescribe short-acting benzodiazepines on an as-needed
(prn) basis when Mr. R starts to get agitated.
D. Prescribe a trial of cannabis (e.g., edibles), presuming
that the patient’s behavior is anxiety related.
E. Prescribe a trial of citalopram for agitation.
Previous alternative interventions initiated by Mrs. R, in-
cluding consultation with faith healers and use of medicinal
cannabis, had been of limited benefit. Aromatherapy, music
therapy, and reminiscence therapy were also attempted with
limited response. Although a day program was attempted
several months before the initial geriatric psychiatry visit,
Mr. R’s screaming and aggressive behaviors led to his being
asked to leave after the first 2 weeks.
After several visits to the geriatric psychiatry clinic,
during which rapport and trust were gradually established
with Mrs. R, the staff discussed nonpharmacologic ap-
proaches with her at length, as well as the risks and benefits
of several classes of medications. Mrs. R eventually agreed to
a trial of an antidepressant medication targeting Mr. R’s
agitation.
On the basis of findings from the Citalopram for Agitation
in Alzheimer’s Disease (CitAD) Study (4), the psychiatrist
prescribed 10 mg citalopram and gradually titrated it up-
ward, over several months, to 40 mg. Unfortunately, this
upward titration was associated with an increase in Mr. R’s
corrected QT (QTc) interval to 492, without an apparent
reduction in agitation intensity or frequency. Citalopram was
subsequently discontinued.
Mrs. R firmly declined consideration of any further
medication trials for nearly 6 months. Ultimately, Mr. R’s
daughter sustained a broken wrist when Mr. R pushed her
while she was providing caregiver support.
Focus Vol. 19, No. 1, Winter 2021
 BECK ET AL.

2.2 What is the most appropriate next step in the manage- Discussion of Case 2
ment of Mr. R’s agitation? (More than one answer may be
Although dementia (i.e., major neurocognitive disorder) is a
appropriate.)
broad category of illnesses defined primarily by a range of
A. Report Mrs. R to Adult Protective Services for neglect cognitive deficits, some of the most challenging and dis-
of an older adult. tressing symptoms for patients and caregivers are the be-
B. Strongly encourage Mrs. R to consent to the patient havioral and psychological symptoms of dementia (BPSD).
being hospitalized to comprehensively assess and ad- These symptoms (also commonly known as neuropsychiat-
dress the behaviors. ric symptoms, or NPS) include psychosis (delusions and
C. Prescribe short-acting benzodiazepines on a prn basis hallucinations), verbal or physical agitation, verbal or
when Mr. R starts to get agitated. physical aggression, depression, anxiety, apathy, disinhibi-
D. Advise Mrs. R that the patient requires a long-acting tion, and wandering (6).
injectable antipsychotic. Mr. R’s case illustrates the numerous complex challenges
E. Obtain an ethics consultation. faced by families who care for their loved ones with de-
mentia who are experiencing BPSD. Clinicians who are
After the episode in which her daughter was injured, Mrs. R
asked to evaluate and manage these patients will inevitably
agreed reluctantly to psychiatric hospitalization of Mr. R for
face numerous ethical questions. In several ways, the
further evaluation and management, with clear communi-
treatment of BPSD represents a perfect storm of ethical di-
cation from the outpatient geriatric psychiatrist that the use
lemmas. First, patients with dementia in the moderate to
of psychotropic medications would be necessary to ensure
advanced stages generally lack adequate capacity to provide
patient and staff safety. She reluctantly agreed to the emer-
informed consent for their own treatment. Second, because
gent use of benzodiazepines, if needed, and was willing to
patients with diminished autonomy such as those with ad-
consider mood-stabilizing medications. However, she was
vanced dementia require surrogates to make medical deci-
unwavering in her refusal to consider use of antipsychotic
sions on their behalf, clinicians find themselves in the
medications after a review of the U.S. Food and Drug Ad-
difficult position of trying to alleviate the patient’s symptoms
ministration (FDA) black-box warning regarding the use of
while helping families navigate this often fraught decision-
antipsychotic medications in dementia (5).
making process. Third, because BPSD can become severe to
During the initial phase of psychiatric hospitalization,
the point where patient and caregiver safety may be in
multiple emergent intramuscular injections of lorazepam
jeopardy, such potential harms must be factored into the
were necessary to mitigate bouts of physical aggression
evaluation of potential harms of treating versus not treating
toward staff. Mr. R also appeared suspicious toward both
the patient psychopharmacologically. Finally, relatively
staff and family members, including his wife, with clear
limited treatment options present challenging trade-offs of
reactions to internal stimuli and apparent misidentification
potential benefits versus risks.
delusions with angry posturing at his mirror image. After
Nonpharmacological interventions are universally rec-
further review of the treatment of psychosis, Mrs. R agreed
ognized as the first-line management for BPSD (7), with
to a trial of low-dose risperidone. However, this brief trial
those based on family caregiver interventions having the
was aborted at her firm request because of the emergence
greatest evidence of benefit. These include interventions
of a resting tremor. Mrs. R also declined further trials of
such as caregiver education and skills training in dementia
antipsychotic or mood-stabilizing medications, despite
care; enhancing support and self-care techniques for care-
multiple family meetings wherein the couple’s children
givers to mitigate burnout; and home environmental re-
noted their belief that Mr. R would not have foregone
design to improve patient safety, minimize their confusion,
treatment of his psychotic symptoms. Consequently, be-
and enrich their sensory stimuli, among others (8, 9).
cause of the need for routine prn doses of lorazepam, which
However, although nonpharmacological interventions
his wife accepted, the patient was started on scheduled
may, over time, be effective in reducing the frequency or
clonazepam. With the scheduled use of 2 mg clonazepam
intensity of BPSD, the immediate benefit of such interven-
twice daily, the patient was ultimately calmer, although
tions is often limited in a person with dementia experiencing
now bedbound and requiring total care. He was discharged
acute agitation or frank psychosis: When patient or caregiver
back to his family’s care at the wife’s request, against
safety and quality of life are in immediate jeopardy, psy-
medical advice.
chotropic medications are generally necessary. Ultimately,
2.3 Which ethical principles was the treatment team trying
both pharmacological and nonpharmacological interven-
to balance in the care for Mr. R and in communication
tions play a crucial role in the optimal management of BPSD,
with Mrs. R?
which an expert consensus panel has described using the
A. Respect for persons, beneficence, and nonmaleficence acronym DICE for describing the symptoms and context
B. Nonmaleficence and beneficence of the behaviors; investigating the contributing factors to
C. Fidelity and respect for persons the behaviors; creating a treatment plan, including both
D. Justice and beneficence nonpharmacological management and—when necessary—

Focus Vol. 19, No. 1, Winter 2021 focus.psychiatryonline.org 55

ETHICS COMMENTARY
pharmacological interventions to ameliorate acute risk of
harm to caregivers or patients or should nonpharmacological
interventions be ineffective; and evaluating whether the
treatment plan has been effective and modifying the plan as
appropriate (7).
The central ethical tension in any treatment intervention
is that between the principles of beneficence (the relief of
suffering, enhancement of quality of life, and harm reduction
to self or others) and nonmaleficence (avoiding harm). This
tension is particularly challenging with psychotropic medi-
cations (i.e., antipsychotics, antidepressants, mood stabi-
lizers, or sedative-hypnotics) in persons with dementia,
given this population’s unique vulnerability to medication
side effects and adverse events as well as their eroding de-
cisional capacity with cognitive decline. Although all psy-
chopharmacologic agents are associated with potential side
effects—even medications as generally benign as selective
serotonin reuptake inhibitors (SSRIs)—some, such as anti-
psychotic medications, are considered particularly risky and
are labeled as such with an FDA black-box warning that
notes the increased risk of stroke and mortality associated
with the use of antipsychotics in persons with dementia (10).
Consequently, psychotropic medications are primarily used
in this population when nonpharmacological interventions
are ineffective in managing BPSD or when there is imminent
risk of harm to the patient or caregivers. Even so, particular
efforts should be taken not only to weigh the anticipated
benefits of a psychotropic medication against the potential
risks but also to conduct an optimal informed-consent pro-
cess with the patient or surrogate decision maker.
One must not presume that patients in the mild or early to
moderate stages of dementia, or even patients with delirium,
completely lack treatment decision-making capacity; none-
theless, as cognitive impairment worsens, decisional capac-
ity invariably wanes, eventually necessitating the use of a
surrogate decision maker. Ideally, this surrogate decision
maker would be the person who best understands the cog-
nitively impaired individual’s clinical situation; most ap-
preciates their life goals and values; and is, consequently,
legally recognized by the cognitively impaired person—
while they maintain the capacity to make such a decision—as
their health care power of attorney. Absent such a formal
designation, most states designate the next of kin as decision
makers, using a hierarchy of relational proximity to the
person in question: typically, the person’s spouse or domestic
partner, then an adult child, a parent, a sibling, then other
relatives or close friends.
Although one hopes that the decisions of the legally
designated decision maker or closest next of kin accurately
reflect not just the patient’s life goals and values but also the
consensus views of the patient’s family and friends, sadly,
this is not always the case. All too often—particularly with
end-of-life decisions—disagreements may arise between
family members and friends regarding the patient’s goals
and values. Such challenges highlight the value of early di-
agnosis of progressive dementing illnesses, which, in turn,
56 focus.psychiatryonline.org
allow time for the frank and timely review of the patient’s
life goals and values that is at the heart of ethically appro-
priate clinical care. Such a discussion is a crucial step in
appropriately balancing the ethical principle of beneficence
against nonmaleficence in a way that best reflects the pa-
tient’s goals and values and thereby respects, as best as
possible, a patient’s autonomy in an illness that all too often
ends in the loss of decisional capacity.
Case 3
BF is a 33-year-old man with a history of schizoaffective
disorder. He is in the psychiatric hospital for psychosis
complicated by medical issues as well as an unusual response
to antipsychotics, including an increase in his creatine kinase.
He has had neuroleptic malignant syndrome on previous
trials of antipsychotics. The inpatient psychiatrist considers a
newer antipsychotic that BF has not yet tried, which has a
unique mechanism of action. However, even with the manu-
facturer’s patient assistance program, the medication costs an
amount that is not feasible for BF and his family to afford.
3.1 Is it ethically justifiable to prescribe this medication if we
know that the patient will not be able to afford it going
forward? Does it depend on how life saving or life
changing the medication potentially is?
A. No. If the medication is beneficial to BF, it would be
devastating to him and his family to not be able to
continue receiving it because of its cost.
B. No. There is no guarantee that the medication would be
helpful, and there is a large possibility that it may even
be harmful, given BF’s past responses to antipsychotics.
C. Yes. The medication may become more affordable in
the near future.
D. Yes. It is up to BF to decide whether he and his family
want to pay for it or find another means in which to
pay for it.
E. Any of the aforementioned responses may be justified.
Of note, the psychiatrist thought of this medication be-
cause of visits from a pharmaceutical representative to his
clinic. The representative gave him a psychiatric textbook,
meals, and office supplies to learn more about the new
medication.
3.2 When is it ethically appropriate for a physician to accept
“gifts” from a pharmaceutical company?
A. It is never appropriate for a physician to receive “gifts”
(pens, meals, etc.) from pharmaceutical companies, as
it will bias the treatment provided.
B. It is sometimes appropriate, as even though bias may
be introduced (11), the physician may learn about the
new treatments that could potentially be helpful to
patients.
C. It is always appropriate, as this will help patients
obtain the best medicine available by teaching phy-
sicians the most up-to-date pharmacotherapies.
Focus Vol. 19, No. 1, Winter 2021

Answers
1.1. A, C, D, E, F, and G are all appropriate responses. It
would be inappropriate to discontinue the alprazolam
and modafinil (choice B) without further information.
1.2. The most appropriate responses are A, B, and D. Choice
C is incorrect, because it may be inappropriate to make
medication changes via phone or messages because the
patient may not be able to fully portray their symptoms
or side effects through these modalities. For the most
comprehensive care, it is best to see the patient in
person, or at least through telemedicine, to be able to
observe the patient’s grooming and hygiene, appear-
ance, behavior, and affect and to assess the patient’s
insight and judgment.
1.3. The best response is D. Autonomy (self-governance)
and beneficence (the responsibility to act in a way that
provides the greatest benefit) best describe the ethical
principles involved. The other responses contain at
least one principle that does not apply.
2.1. The best responses are B and E. Optimal management
of a patient with behavioral and psychological symp-
toms of dementia (BPSD) has been described using the
acronym DICE. This entails a comprehensive de-
scription of the behavioral changes associated with
dementia; a careful investigation into the various fac-
tors that may be triggering a patient’s behavioral de-
cline from their former baseline; creation of a treatment
plan initially involving primarily nonpharmacological
interventions but also potentially pharmacological
treatment when clinically indicated; and, finally, eval-
uation and modification of the treatment plan based on
its effectiveness. As depression is a common—but not
always easily identified—driver of behavioral issues in
dementia, and SSRIs are generally a low-risk and ef-
fective intervention in these cases (as found in the
CITAD Study), an early trial of citalopram for BPSD is
often indicated.
2.2. The best response is B. A comprehensive evaluation of
the behavioral changes and identification of potential
triggers is often best achieved during a psychiatric
hospitalization, particularly when the behavioral issues
are unmanageable in the home environment or poten-
tially jeopardize the patient’s or caregiver’s safety.
Although Mrs. R declined the initial treatment rec-
ommendations of providers, she did not demonstrate
decisional incapacity in this decision and otherwise
was meeting the basic needs of the patient and taking
steps to ensure his safety; consequently, an Adult Pro-
tective Services report for neglect is unwarranted. Al-
though prn use of benzodiazepines may be necessary at
times for emergent management of behaviors that
threaten the safety of the patient or care providers,
they are best used in a structured, supervised setting,
as the risks associated with these medications may
Focus Vol. 19, No. 1, Winter 2021
BECK ET AL.
outweigh benefits. Similarly, although antipsychotic
medications may be necessary and effective as both prn
and scheduled medications, they are best used in acute
management of behaviors that jeopardize safety or limit
necessary care, and attempts should be made to limit or
discontinue medications once the crisis has resolved.
Therefore use of long-acting injectable antipsychotic
medications is rarely warranted.
2.3. The best response is A. The central ethical tensions in
managing the behavioral and psychological symptoms
of dementia are those arising among the principles of
beneficence (improving patient quality of life, including
advancing goals of safety and security in one’s sur-
roundings), nonmaleficence (avoiding or minimizing
actions that might cause harm to the patient or others),
and respect for the patient’s autonomy, including in in-
stances such as this one, protecting patients with di-
minished autonomy. Frank discussions with patients,
families, and others involved in the patient’s care about
this delicate, often difficult, ethical balancing act—in-
cluding the acknowledgment that there are inherent
risks and trade-offs in any decision—are best done as
early as possible, while decisional capacity is still largely
maintained. Despite the best efforts of clinicians, these
discussions often are necessary later in the course of
illness and, as this case illustrates, may be particularly
challenging and complex at these later stages.
3.1. The best response is E. Any of the responses listed may
be justifiable responses; there is no “correct” answer.
This plays into the art of ethics itself, as one must
weigh the risks and benefits of all possibilities for each
case while simultaneously holding several potentially
opposing solutions.
3.2. The best response is B. Although there are long-
standing concerns about the potential effect of financial
interests on medical decision making (12), the physi-
cian may also learn about new treatments and mecha-
nisms of action that could be very helpful to patients.
AUTHOR AND ARTICLE INFORMATION
Department of Psychiatry and Behavioral Sciences, Stanford University,
Stanford, California (Beck, Kim, Dunn). Send correspondence to Dr.
Dunn (laura.dunn@stanford.edu).
Dr. Dunn receives royalties from American Psychiatric Association
Publishing. The other authors report no financial relationships with
commercial interests.
Focus 2021; 19:53–58; doi: 10.1176/appi.focus.20200043
REFERENCES
1. Gutheil TG: Reflections on ethical issues in psychopharmacology:
an American perspective. Int J Law Psychiatry 2012; 35:387–391
2. Roberts LW, Jain S: Ethical issues in psychopharmacology. Psy-
chiatr Times 2011; 28(5). https://www.psychiatrictimes.com/view/
ethical-issues-psychopharmacology Accessed Sept 25, 2020
3. Dell ML, Vaughan BS, Kratochvil CJ: Ethics and the prescription
pad. Child Adolesc Psychiatr Clin N Am 2008; 17:93–111, ix
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ETHICS COMMENTARY
4. Porsteinsson AP, Drye LT, Pollock BG, et al: Effect of citalopram
on agitation in Alzheimer disease: the CitAD randomized clinical
trial. JAMA 2014; 311:682–691
5. Jibson MD: Second-generation antipsychotic medications: pharma-
cology, administration, and side effects. UpToDate. https://www.
uptodate.com/contents/first-generation-antipsychotic-medications-phar-
macology-administration-and-comparative-side-effects?search=
second-generation-antipsychotic-medicationspharmacology-admin-
istration-and-side-effects&source=search_result&selectedTitle=1;
150&usage_type=default&display_rank=1. Accessed Sept 30, 2020
6. Zhao QF, Tan L, Wang HF, et al: The prevalence of neuropsychi-
atric symptoms in Alzheimer’s disease: systematic review and
meta-analysis. J Affect Disord 2016; 190:264–271
7. Kales HC, Gitlin LN, Lyketsos CG: Assessment and management of be-
havioral and psychological symptoms of dementia. BMJ 2015; 350:h369
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8. Brodaty H, Arasaratnam C: Meta-analysis of nonpharmacological in-
terventions for neuropsychiatric symptoms of dementia. Am J Psy-
chiatry 2012; 169:946–953
9. Livingston G, Kelly L, Lewis-Holmes E, et al: Non-pharmacological
interventions for agitation in dementia: systematic review of
randomised controlled trials. Br J Psychiatry 2014; 205:436–442
10. Schneider LS, Dagerman KS, Insel P: Risk of death with
atypical antipsychotic drug treatment for dementia: meta-
analysis of randomized placebo-controlled trials. JAMA 2005;
294:1934–1943
11. Wazana A: Physicians and the pharmaceutical industry: is a gift
ever just a gift? JAMA 2000; 283:373–380
12. Baker CB, Johnsrud MT, Crismon ML, et al: Quantitative analysis of
sponsorship bias in economic studies of antidepressants. Br J Psy-
chiatry 2003; 183:498–506
Focus Vol. 19, No. 1, Winter 2021

COVID-19 and the Doctor-Patient Relationship
David C. Fipps, D.O., and Elisabet Rainey, M.D.
During a pandemic, physicians can become so inundated
with combating the disease that they may forget the
individual patient’s experience. In this perspective, the
authors describe a case of COVID-19 from the point of
view of the grief stages (or categories) described by
We present a commentary stemming from the care and in-
terview of a 29-year-old African American male—Mr. V—who
contracted coronavirus disease 2019 (COVID-19) during the
crux of a pandemic, a time of isolation and fear. During such a
crisis, we medical professionals often direct our attention
toward society as a whole in an attempt to slow the rate of
spread and determine appropriate interventions. Although
these needs are essential, this focus can often distract us from
the personal experience of the individual patient. To this end,
instead of following the minute pathophysiologic details of
Mr. V’s symptomatic progress, hospitalization, treatment and
recovery, we focus on Mr. V’s personal response to his
COVID-19 experience. In this discussion, we intertwine a
commentary of empathy, compassion, and humanistic care to
reiterate the value of the vital role of the doctor-patient re-
lationship during a crisis. We utilize a categorical sectioning
method to distinguish different emotional responses based on
the grief stages described by Kübler-Ross (1). Identifying in-
formation has been changed to protect patient privacy.
DENIAL
Originally, when Mr. V began developing fatigue, body aches,
and chills, he considered the possibility of a coronavirus in-
fection but eventually concluded that his symptoms were sec-
ondary to a detoxification diet. Considering the stigma
surrounding contracting coronavirus, individuals may display
denial by assuming that they would never get the virus or that
their symptoms are simply from allergies or the flu. This denial
may diminish upon receiving a positive diagnostic test. Un-
fortunately, Mr. V’s positive diagnostic test did not result until
after he was hospitalized for respiratory distress and pneumonia.
Denial is not always pathologic; it can be adaptive or
maladaptive. Adaptive denial can protect the individual from
being emotionally overwhelmed, whereas maladaptive denial
is counterproductive and can prevent or delay care. Denial is
not always rejecting the diagnosis; it could include minimizing
Focus Vol. 19, No. 1, Winter 2021
21ST-CENTURY PSYCHIATRIST
Elizabeth Kübler-Ross, with an emphasis on utilizing skills
to enhance the doctor-patient relationship even in this
time of crisis.
Focus 2021; 19:59–60; doi: 10.1176/appi.focus.20200033
the symptom severity, avoiding or delaying care, or having little
to no emotional reaction to symptoms (2). If denial becomes
problematic, physicians should ensure respectful and direct
communication about the illness, prognosis, and treatment
while reassuring patients that they will not be abandoned.
ANXIETY AND ANGER
Mr. V recalled that, as his symptoms progressed to severe
fatigue and exertional dyspnea, he became quite fearful and
anxious. His fatigue caused fears of falling and being trapped
on the floor, and his anxiety progressively worsened over
time as he sought care four times before receiving the ac-
curate diagnosis and admission to the hospital. This delay in
care acted as a stimulus for anger and brought about ques-
tions such as, “Why me?” and “Why is this happening?”
A lethal pandemic can instill anxious thoughts even for
those without anxiety at baseline. It forces individuals to
realize their vulnerabilities and potential mortality. In ad-
dition, contracting an illness can make one feel defective,
weak, less desirable, and further isolated. The highly encour-
aged social isolation can produce a sense of disconnection and
precipitate fears of abandonment. Blanket reassurance is typi-
cally ineffective and could be detrimental if the patient per-
ceives it as patronizing or superficial. Empathy and reassurance
that focuses on the individual’s specific fears can offer a more
humanistic method for relief.
Anger is a common response for people dealing with an
illness. Unfortunately, it may be one of the most difficult
responses to confront as physicians. Conveying empathy
with necessary boundary setting and tactful redirection are
often essential when dealing with the angry individual. Con-
ceptualizing a patient’s anger as a natural occurrence and
attempting to diffuse and redirect the anger can help to rees-
tablish a collaborative relationship. Physicians should recog-
nize that anger may represent a patient’s desire for control in a
time where chaos and a lack of control are nearly ubiquitous.
focus.psychiatryonline.org 59
21ST-CENTURY PSYCHIATRIST
DEPRESSION AND GUILT
After the anger, anxiety, and shock of his diagnosis subsided,
Mr. V experienced sadness when having to face his potential
mortality at a young age. Mr. V had no chronic medical conditions
other than morbid obesity (with a body mass index of 43), was
not prescribed medications other than to treat his COVID-19, and
had no major diseases in his family. Therefore, facing his potential
death was an unfamiliar and daunting concept. In addition, the
loss of independence and his ability to care for himself during
hospitalization amplified his depressive thoughts, and he began
internalizing his guilt and asking, “Am I responsible for this?”
Depression, sadness, and a sense of loss are quite common
for individuals with medical illness. Sadness is not always
pathognomonic of major depressive disorder and may simply be
a manifestation of adjustment to one’s illness. These symptoms
could be a reaction to how the illness has affected the individ-
ual’s life or from anticipation of future impact. Recognizing the
parallels to the process of mourning can be of great benefit, as it
allows patients to normalize their sadness (3). In this context,
someone who is mourning needs support, hope, and time to
process. Providing false hope is not recommended; however,
giving a realistic viewpoint (e.g., giving examples of similar
presentations with positive outcomes) could be of great value.
As physicians, we can instill hope and understand that time to
process is a vital component of addressing this stage of grief.
Guilt is particularly pertinent to the present pandemic.
Considering the highly publicized necessity of social iso-
lation, self-quarantine, hygiene techniques, and so forth,
when one does contract coronavirus, one could internalize
the blame. This often results in asking, “If I had done more,
could this have been avoided?” and “Am I a danger to my
family?” It is important for physicians to take a non-
judgmental stance to avoid the counterproductive, critical,
and disapproving responses. Such negative reactions are
typically ineffective for motivating behavioral change. Even
if the patient is clearly at fault (e.g., lack of social distancing),
taking a nonjudgmental viewpoint and approaching feelings
of guilt with compassion can open up a trusting relationship
for discussions of future preventative behavioral changes.
BARGAINING AND OUTREACH
As a religious man, Mr. V reached out in prayer and consid-
ered atonement that he could provide in exchange for a cure.
During this time, when he still had strength, he reached out to
social media for support, which, he later noted, provided
more than he could handle. In fact, he eventually asked
friends to stop sending messages so that he could rest.
Individuals with any illness can undergo feelings of help-
lessness and a lack of control. Their attempts to minimize their
distress can include bargaining with a higher power (a spiritual
being, a physician, etc.) or reaching out for social support. So-
cial media has expanded the significance and impact of this
stage of grief since Kübler-Ross’s time. For some like Mr. V,
social media brings about an encouraging social support; for
60 focus.psychiatryonline.org
others, it can exacerbate anxiety and catastrophic thinking.
Some patients in this stage may even treat the doctor as an
infallible being and hope that their compliance, nonquestioning
attitude, and respectful demeanor will bring better, more suc-
cessful treatment. It is best for physicians in such situations to
make clear that they will take care of the individual regardless
of his or her actions. It is also valuable to bring back some
semblance of control by allowing the patient to be an active
member of the decision-making process, if possible.
ACCEPTANCE
Eventually, Mr. V was able to accept the diagnosis and find
relief in knowing what underlying condition caused his
symptoms. This stage became more easily attainable for Mr.
V, as his hospitalization progressed toward positive out-
comes for his pneumonia and COVID-19 symptoms.
Acceptance is a broad concept, with many different con-
texts, and unfortunately, it is not always guaranteed. When
describing acceptance in the context of death, one becomes
more comfortable with the concept of their own mortality.
When death is no longer in the near future—because of an
improving clinical picture, for instance—acceptance can often
emerge naturally. As physicians, we should hope for acceptance
but not always expect it. Clearly, acceptance comes on a case-
by-case basis and can be greatly influenced by social support,
spirituality, mental health, prognosis, and so forth.
CONCLUSIONS
In conclusion, when mass fear and anxiety are common-
place, such as during a pandemic, we as physicians can be-
come so focused on combating the disease that we may forget
the individual patient’s experience. We must remember that
patients are individuals and not just the diagnoses that they
may receive. Remembering Mr. V’s experience can bring a
focused empathy when treating patients with COVID-19 and
enhance the doctor-patient relationship. This will go a long
way, both in direct patient care and the milieu of the health care
experience. As with most cases of hospitalization, COVID-19
survivors will likely reflect on this time and value the interac-
tions with their doctors far more than the specifics of the
treatment received.
AUTHOR AND ARTICLE INFORMATION
Mayo Clinic, Rochester, Minnesota (Fipps); Prima Health-Upstate, Uni-
versity of South Carolina, Greenville (Rainey). Send correspondence to
Dr. Fipps (dfipps123@gmail.com).
No outside funding was obtained for the study.
The authors report no financial relationships with commercial interests.
REFERENCES
1. Kübler-Ross E: On Death and Dying. New York, Macmillan, 1969
2. Goldbeck R: Denial in physical illness. J Psychosom Res 1997; 43:
575–593
3. Fitzpatrick MC: The psychologic assessment and psychosocial recovery
of the patient with an amputation. Clin Orthop Relat Res 1999; 361:98–107
Focus Vol. 19, No. 1, Winter 2021

Integrating Diversity, Equity, and Inclusion Into an
Academic Department of Psychiatry and
Behavioral Sciences
Nadine J. Kaslow, Ph.D., Ann C. Schwartz, M.D., Dinah K. Ayna, Ph.D., Negar Fani, Ph.D., Betsy Gard, Ph.D.,
David R. Goldsmith, M.D., Joya Hampton-Anderson, Ph.D., Jennifer Holton, M.D., Erica D. Marshall-Lee, Ph.D.,
DeJuan White, M.D., Jordan E. Cattie, Ph.D.
This article highlights one department’s efforts to bolster
diversity, equity, and inclusion as an exemplar for other
academic departments. It offers an approach for building an
infrastructure and leadership group and details accomplishments
associated with strategic plan priorities related to visibility,
values, stakeholder education, recruitment, retention,
promotion, and community engagement. It also delineates
In this 21st century, academic psychiatry departments must
prioritize diversity, equity, and inclusion (DEI). Such trans-
formation is in keeping with national calls to implement
policies that foster diversity and ensure a culturally com-
petent workforce to provide optimal care for a diverse pa-
tient population (1). To empower other departments of
psychiatry and behavioral sciences to bolster DEI, this arti-
cle describes the infrastructure and accomplishments from
one such department, discusses DEI-related challenges and
strategies to overcome them, and reflects on next steps.
Recommendations are proffered for building DEI programs
that can be adapted to the broader ecological context in
which each department is embedded; our efforts occurred
within a school of medicine and a university that valued DEI
but did not place it central to their mission—a culturally rich
local community on the forefront of social justice in a region
that did not prioritize these values consistently.
INFRASTRUCTURE AND LEADERSHIP GROUP
In 2017, the Department of Psychiatry and Behavioral Sci-
ences at our university formed the Diversity and Inclusion
Subcommittee (DISC), which includes faculty, trainees, and
staff selected by the vice chairs who had previous DEI re-
sponsibilities. The committee members represent diversity
related to professional degree, primary work site, age, gen-
der, gender identity, race, ethnicity, culture, national origin,
religion, sexual orientation, ability status, primary language,
immigrant status, and family socioeconomic status. This
committee may be expanded in the future to include other
Focus Vol. 19, No. 1, Winter 2021
21ST-CENTURY PSYCHIATRIST
challenges encountered in transforming a departmental
culture to one that is more diverse, equitable, and inclusive
and strategies for overcoming these challenges. Finally, it
discusses next steps and recommendations for other
academic departments.
Focus 2021; 19:61–65; doi: 10.1176/appi.focus.20200024
stakeholders, such as patients and community members.
Spearheaded by the Vice Chair for Faculty Development
with the support and input of the chair and other senior
leaders of the psychiatry department, the DISC created a
mission, a goals statement including values, and a logo. Its
mission statement reads: “The Department . . . welcomes,
respects, and embraces differences in age, sex and gender,
sexual orientation, gender identity, race, ethnicity, in-
digenous background, culture, national origin, language,
religion, spiritual orientation, ability status, social class, ed-
ucation, veteran status, political persuasion, professional
interests, and other cultural and professional dimensions.
We celebrate intersectionalities among these cultural and
professional dimensions. The DISC endeavors to foster an
equitable and inclusive culture in which all members of the
department feel respected, valued, and recognized for their
unique and collective contributions.”
In keeping with the DISC’s strategic plan, several related
work groups were formed. One year after the DISC was
established, to enhance the experience of and to empower
diverse faculty, the Women’s Faculty Subcommittee (WFS)
and the Racial, Ethnic, and Cultural Minority Faculty Sub-
committee (RECM) were formed. These two cochaired
subcommittees outlined their own missions and goals. The
mission of the WFS is to “promote a culture that actively
supports the successful professional and personal develop-
ment of all women faculty in our department through edu-
cation, advocacy, and mentoring.” The mission of the RECM
is to “promote awareness of issues related to race, ethnicity,
and culture among the faculty in our department, and
focus.psychiatryonline.org 61
INTEGRATING DIVERSITY, EQUITY, AND INCLUSION INTO AN ACADEMIC PSYCHIATRY DEPARTMENT
provide a source of safety and support, education and other
resources.” The following year, the Resident Diversity
Committee, was created to advance diversity initiatives
within the residency program.
To bolster the departmental DEI portfolio and obtain
the personnel to implement the strategic plan, the DEI in-
frastructure was expanded. In 2019, two assistant Vice
Chairs for Diversity and Inclusion were selected by senior
leaders of the psychiatry department. They assumed lead-
ership roles vis-à-vis key components of the diversity stra-
tegic plan, and their responsibilities evolved based on their
interests and expertise and departmental needs. The Vice
Chair for Faculty Development’s scope was broadened; she
became Vice Chair for Faculty Development, Diversity, Eq-
uity, and Inclusion and was allotted a small annual budget.
The vice chair, assistant vice chairs, and subcommittees’
cochairs formed a Diversity Leadership Council to learn
from one another and to collaborate to expand their impact.
Members of this council determine fiscal priorities for the
diversity budget.
ACCOMPLISHMENTS RELATED TO STRATEGIC
PLAN PRIORITIES
Prioritized Visibility
To ensure visibility, each subcommittee maintains an In-
ternet presence and advertises events in the monthly de-
partmental newsletter. The subcommittees jointly host an
annual event in which faculty mingle and make recom-
mendations for culture transformation. The three subcom-
mittees (DISC, WFS, RECM) jointly created an annual
award to recognize a faculty leader who exemplifies the
department’s DEI mission. The subcommittees cosponsor
departmental initiatives that bring together the arts and
sciences from throughout the university to model ways di-
versity can be interwoven into academic activities; for ex-
ample, the RECM cofacilitated the conversation about
culture change by hosting an event on poetry and psychiatry
that featured a Pulitzer Prize winning African American
poet. Activities such as these bolster external visibility.
The subcommittees increasingly have been recognized
for their efforts. Within the department, people have re-
ported improved interactions, greater inclusion of diverse
faculty on committees, and appointment of diverse faculty
to lead strategic initiatives. Within the broader community,
there are growing requests for Diversity Leadership Council
members to engage in medical school and university efforts
(e.g., regarding unconscious bias). Such visibility reduces
marginalization and increases the impact of faculty com-
mitted to diversity.
Conveyed Values
Crucial to the success of the DEI efforts is articulation of the
values that guide action. One way in which the values of
accepting and celebrating difference have been conveyed is
through development and dissemination of departmental
62 focus.psychiatryonline.org
emails following the perpetration of hate crimes. Con-
structed by a DISC subgroup, including someone associated
with the targeted group, these emails describe the incident,
honor the victims, offer strategies to mitigate the devastating
impacts on communities, and convey the unacceptability of
the prejudice. These values also are evidenced in efforts to
encourage department members to add personal gender
pronouns to their e-mail signatures and departmental web-
pages. Members of the department appreciate these dem-
onstrations of allyship and hope for a more inclusive culture
that gives all voices equitable power.
A second way in which values have been conveyed is
by acknowledging and addressing microaggressions. After
microaggressions transpired at an event attended by de-
partment members, the Diversity Leadership Council and
subcommittees hosted a well-attended (.150) forum. Small
group discussions were cofacilitated, and individuals not
previously involved in DEI conversations participated.
Recommendations for culture change that came from the
forum are being incorporated into the department’s strategic
plan implementation efforts.
A third way in which our values have been conveyed
pertains to efforts to ally with, advocate for, and engage in
science-informed activities to improve the quality of life for
members of the department, the patients served, and the
communities with whom we partner (2). The Diversity
Leadership Council and other committee members have
facilitated diversity dialogues for faculty, staff, and trainees
(e.g., psychiatry residents and fellows, psychology interns
and postdoctoral residents, basic science postdoctoral fel-
lows) in response to recent racially related social injustices
in our nation and have trained others to engage in this
process.
Educated Stakeholders
One powerful educational initiative we have implemented
is the diversity moment at each DISC meeting, in which
members share a story about oppression, discrimination, or
marginalization related to their social identities or evolving
cultural humility (3). Subcommittee members have found
learning through listening to personal experiences to be
more poignant and effective than traditional educational
activities and more likely to increase trust and engagement.
A second educational initiative implemented has been the
securing of annual grand rounds spots to invite experts to
speak and expand awareness and sensitivity about DEI.
Speakers have given presentations on Muslim mental health,
transgender behavioral health, and implicit bias in health
care and have provided consultation services to the sub-
committees for initiatives.
A third set of initiatives has involved the subcommittees’
facilitation of panel discussions, workshops, journal clubs,
and movie groups. These programs have centered on un-
conscious bias, microaggressions, and microinterventions
(4); transgender health care; and leadership competencies
that attend to gender and privilege.
Focus Vol. 19, No. 1, Winter 2021

A fourth initiative has been to include information in the
department newsletter about diversity-related topics. Indi-
viduals identified with a particular sociodemographic group
have provided background information and shared their
personal experiences about cultural observances (e.g., Yom
Kippur, Ramadan, Martin Luther King Jr.’s birthday). Re-
cently, weekly updates have been shared about disparities
and COVID-19.
Fifth, a diversity consultation service has been created to
identify departmental consultants on topics including race,
ethnicity, language, disability, religion, sexual orientation,
sexual identity, refugees and immigration, and implicit bias.
Consultants have provided cultural input related to patient
care, education, or research. For example, a faculty member,
whose patient identified as Muslim and transgender, re-
ceived consultation from a resident regarding empowering
the patient within their (preferred pronoun) family and re-
ligious community.
To foster faculty members’ professional development,
department members have partnered with an academic
psychiatry department in Ethiopia to implement a global
virtual learning collaboration focused on innovative tech-
nologies to enhance teaching (5). Topics have included
learning management systems, innovative technology-based
presentations, technological innovations in psychotherapy
supervision, and social media to bolster learning.
To strengthen resident training, the curriculum was re-
vised to expand the diversity focus. Sessions were added on
cultural formulation, interface between the cultural identi-
ties of the residents and their patients, religion and spiritu-
ality, and culturally informed interventions.
Bolstered Recruitment, Retention, and Promotion
To promote DEI in recruiting faculty and trainees, several
changes were made. To make training programs more in-
viting, websites and training materials (e.g., for welcoming
international trainees and highlighting pertinent resources)
were updated. A DISC member now participates in all re-
cruitment activities to detail the departmental commitment
to DEI.
For retention purposes, the DISC and the Resident Di-
versity Committee developed a diversity contact list that is
provided annually to all members of the department. This
list features faculty, trainees, and staff who identify with
various social identities (6) so people can network with
others who share or are familiar with specific social identi-
ties and are able to connect them with community resources.
Representatives from DISC, RECM, and WFS attend ori-
entations for new faculty to highlight their presence on
campus and role as resources. The WFS distributes a re-
source guide they created to address issues that may be
particularly relevant for women. Retention is prioritized via
the subcommittees’ emphasis on providing safe places to
discuss DEI challenges and offer opportunities to collabo-
rate for positive change. Because institutional culture and
climate influence retention (7, 8), safe spaces enable people
Focus Vol. 19, No. 1, Winter 2021
KASLOW ET AL.
to gain support from and take action with others with similar
goals and values.
To address faculty promotion, RECM and WFS held joint
meetings to review promotion guidelines and strategies
for career enhancement. WFS has a standing agenda item
for sharing successes and offering professional advance-
ment opportunities to provide a forum for practicing self-
promotion and securing support for career development.
The three faculty subcommittees have a systematic nomi-
nation process for departmental, medical school, univer-
sity, and community awards that has resulted in recognition
of more women and minority faculty. To facilitate the
promotion of diverse individuals, the DISC, RECM, and
WFS provide outlets for supported scholarship and leader-
ship. Faculty and trainees associated with the subcommit-
tees have coauthored publications on DEI (9). Subcommittee
participation has led to increased engagement in research;
one RECM cochair has become involved in multisite re-
search addressing microaggressions and professional iden-
tity formation of underrepresented groups in academic
medicine. Subcommittee leadership roles have led to lead-
ership opportunities in the medical school and in regional
organizations. For example, one WFS cochair created
and chairs a women’s committee for the state psychiatric
society. Finally, senior faculty who represent one or
more forms of diversity now get together annually to cele-
brate promotion and leadership accomplishments (e.g.,
endowed chairs).
Engaged in Community Activities
DISC members have engaged with the community by pro-
viding education and service, primarily centered on the
refugee and asylum-seeking community (e.g., by volunteer-
ing at a local summer camp for refugee and immigrant youth
and providing workshops on pertinent topics, such as ac-
culturation); by participating in a summit on community
challenges and services needed by refugees and asylum
seekers; by partnering with community groups, other uni-
versity departments, and nonprofit community legal pro-
viders to develop a consortium to meet the diverse needs
of asylum seekers within the rubric of the “Physicians for
Human Rights” virtual training, mentoring, and supervi-
sion model; and by collaborating with local organizations
to write grants supporting the provision of mental health
services.
The DISC also hosted a program for the department and
community that centered on the reading by the authors, who
are current or former medical school faculty, of a children’s
book on racial injustice (10). Following the reading, DISC
members specializing in child and/or adolescent psychiatry
or psychology interacted with the children and discussed
with the adults how to help their children recognize and
cope with prejudice and inequity. In a third example of a
community activity, subcommittee members lead seminars
about DEI for trainees, nonprofit groups, and community
members.
focus.psychiatryonline.org 63
INTEGRATING DIVERSITY, EQUITY, AND INCLUSION INTO AN ACADEMIC PSYCHIATRY DEPARTMENT

CHALLENGES ENCOUNTERED IN TRANSFORMING A inform future activities designed to support culture change
DEPARTMENTAL CULTURE (11, 12). Optimally, transparency about assessment findings
will stimulate discussion, garner buy-in from more stake-
Despite these accomplishments, several challenges have
holders, and motivate organizational change. More coura-
complicated efforts to achieve subcommittee missions and
geous conversations will be planned to facilitate and empower
infuse DEI values into departmental systems, practices, and
everyone to speak and hear the voices of all parties. Such
culture. Although our aim is to foster a culture of open di-
communication may include small group discussions, mech-
alogue, some individuals have been reluctant to speak; some
anisms for anonymous suggestions, and in-person DEI con-
fear that being vulnerable could be risky and result in ret-
sultations. Increased activities outside the workplace for
ribution, and others are concerned they might offend
faculty from underrepresented backgrounds could promote
esteemed colleagues or those in power. Others do not appear
collegiality and connection and reduce isolation and margin-
to be invested in such conversations, possibly because they
alization (13). Data could be used to advocate for resources
do not share or prioritize the DEI values enumerated above.
(money, staff ) to advance the DEI agenda. Supporting col-
These challenges limit the diversity of perspectives offered.
leagues’ engagement in DEI to mitigate against burnout and
Even among people committed to advancing DEI, chal-
optimize resilience will be a priority.
lenges emerge in the discourse which need to be navigated.
After 2 years of working to align values, the DISC struggled
to issue a statement about a hate crime that was perceived RECOMMENDATIONS FOR OTHER ACADEMIC
differently by individuals from diverse backgrounds. Instead DEPARTMENTS OF PSYCHIATRY
of glossing over the complexities or avoiding making a
DEI must be integrated within the department’s mission. An
statement, the subcommittee built respect and trust by ac-
infrastructure must be established to foster conversation and
knowledging the process, seeking commonalities, and issu-
strategic plan implementation. Leaders must be trained and
ing a statement about the struggle to reach consensus. As
encouraged to create a community in which all parties ac-
another example, although many DISC members support
knowledge their biases and commit to strengthening their
the use of preferred pronouns to promote inclusion (e.g.,
DEI competencies; action plans are implemented and eval-
“they and them”), this change was challenging for some
uated; and structures and systems that perpetuate bias and
members, because it departs from historical ways of com-
discrimination are altered.
municating in certain languages.
One problem encountered across settings pertains to the
fact that despite widespread departmental interest in DEI CONCLUSIONS
efforts, many people do not engage with the initiatives. For
It is our hope that sharing the initiatives undertaken within
efforts to advance, greater participation is needed by more
our academic department of psychiatry will allow others to
parties, including leaders. In addition, it is challenging to
build on this example. Promotion of DEI is an ongoing col-
identify the best actions to take to promote DEI. After the
laborative process to ensure that all department members
departmental forum that resulted in a list of potential ac-
feel welcome, included, heard, respected, and valued. Our
tions, prioritizing action steps has been complicated.
future efforts will assess the outcomes of our strategic plan
Data are needed to determine the department’s current
and the impact of our DEI efforts and will articulate dy-
state and to capture change. Data collection could allow for
namically evolving best practices.
examination of discrepancies between what people believe
they know about an aspect of cultural competence and their
AUTHOR AND ARTICLE INFORMATION
actual knowledge regarding a specific aspect (e.g., trans
Department of Psychiatry and Behavioral Sciences, Emory School of
and/or gender diversity) of cultural competence before and Medicine, Atlanta (Kaslow, Schwartz, Fani, Gard, Goldsmith, Hampton-
after a training session. However, data related to cultural Anderson, Holton, Marshall-Lee, White, Cattie); Department of Psychi-
competence often are hard to gather or access, and their atry, American University of Beirut Medical Center, Beirut, Lebanon
reliability may be questionable. Finally, although we are (Ayna). Send correspondence to Dr. Kaslow (nkaslow@emory.edu).
grateful for the funding we have received for activities, the The first, second, and last authors assumed primary responsibility for
funds have been limited. The impact of the DEI efforts preparation of the article. The remaining authors are listed alphabetically
and contributed equally.
enumerated above would be greater if additional resources
The authors thank the department chair and members of the three di-
were available.
versity subcommittees for their engagement in diversity, equity, and
inclusion initiatives.
NEXT STEPS The authors report no financial relationships with commercial interests.

Future efforts will be dedicated to creating and embarking

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focus.psychiatryonline.org 65
APPLIED ARMAMENTARIUM
Never Say Never: Successful Clozapine Rechallenge
After Multiple Episodes of Neutropenia
Michael Shuman, Pharm.D., Lori Moss, M.D., Adam Dilich, Pharm.D.
Clozapine is a second-generation antipsychotic with a
superior efficacy for the management of treatment-resistant
schizophrenia but underutilized because of potential side
effects. A 59-year-old Caucasian male veteran was
transferred from the long-term care unit to the acute
psychiatry unit because of suicidality. He was noted as
having a long-standing history of psychosis with significant
referential and paranoid delusions. He had experienced
two previous trials of clozapine; although he had significant
response in the past, both trials ended in neutropenia and
an absolute neutrophil count ,500 cells per microliter,
despite the second trial also including supplemental “as-
needed” doses of pegfilgrastim to manage decline in
Clozapine is a second-generation antipsychotic with supe-
rior efficacy for the management of treatment-resistant
schizophrenia and evidence for the improvement of psy-
chotic symptoms associated with other conditions, such as
schizoaffective disorder or bipolar disorder (1, 2). Furthermore,
it has a noted effect of decreasing suicidality (3). However,
potential side effects include myocarditis, metabolic syndrome,
and neutropenia (absolute neutrophil count [ANC] ,1,500/mL)
(4). Although agranulocytosis (ANC ,500/mL; now replaced
with the term “severe neutropenia”) was noted in less than 1%
of all clozapine recipients after up to 1.5 years of treatment, the
annual rate of neutropenia has been found to be 2.7% and
highest within the first 18 weeks of therapy (5, 6). To address
concerns of neutropenia, in September 2015, a Risk Evaluation
and Mitigation Strategies program was established within the
United States to ensure that a complete blood count (CBC) with
differential is obtained weekly for the first 6 months of therapy
and then every 2 weeks for an additional 6 months; at that
point, monitoring occurs monthly thereafter for the duration of
the clozapine regimen (7).
PATIENT HISTORY
In October of 2017, a 59-year-old Caucasian male veteran
(post-Vietnam era) with a history of paranoid schizophrenia,
depressive disorder not otherwise specified (NOS), cognitive
disorder NOS, traumatic brain injury, anxiety, coronary artery
disease, and cerebrovascular accident was transferred from
66 focus.psychiatryonline.org
neutrophil counts. This particular strategy of filgrastim
use was determined to be a weakness of the second trial. A
PubMed search identified recent literature that discussed
preemptive dosing of filgrastim to prevent neutropenia. Thus, a
protocol was established to administer 300 mg filgrastim
subcutaneously, three times weekly, concurrently with
clozapine initiation. This plan was discussed on local and
national levels to achieve consensus before its initiation. Using
a revised, patient-specific protocol led to successful initiation
of clozapine and the ability to maintain the regimen for over
24 months without interruption or any further suicidal ideation.
Focus 2021; 19:66–70; doi: 10.1176/appi.focus.20200029
the long-term care unit to the acute psychiatry unit because of
suicidality with plans to hang himself by his pajama bottoms.
He was noted as also having a long-standing history of psy-
chosis with significant referential and paranoid delusions
regarding staff and other veterans who, he felt, wanted him to
be kicked off the unit and were stealing his belongings. At the
time, his psychotropic regimen included 15 mg olanzapine at
bedtime and 2.5 mg twice a day (BID) as needed, as well as
60 mg aripiprazole daily. The patient was also receiving 34 mg
pimavanserin daily as an adjunct for psychotic symptoms. He
was noted as having trialed numerous psychotropic agents in
the past, with lack of sustained success, including aripipra-
zole, carbamazepine, citalopram, divalproex, fluphenazine,
haloperidol, lurasidone, minocycline, mirtazapine, nefazo-
done, olanzapine, paroxetine, phenelzine, quetiapine, risper-
idone, and trifluoperazine. He refused electroconvulsive
therapy, noting minimal response in the past. He and his
providers noted that, in previous years, his symptoms had
been less pronounced on clozapine, although not completely
absent and not requiring admission to the acute psychiatry
unit. Thus, clozapine was again considered after first factoring
in the results of previous trials and current suicidal ideation.
CLOZAPINE TRIAL 1 (2005–2014)
The veteran was previously maintained on clozapine suc-
cessfully for 9 years, reaching a maintenance dose of 250 mg
twice daily. However, upon routine monthly monitoring in
Focus Vol. 19, No. 1, Winter 2021

April 2014, his ANC was noted to have decreased from a
baseline range of 2,200–3,200/mL to 1,600/mL with no
ascertained source, including medication changes. Moni-
toring of the CBC with differential increased to twice
weekly, pursuant to the monitoring recommendations at the
time. Three days later, the ANC was noted to be 1,300/mL.
Clozapine was discontinued, and twice weekly monitoring
of the CBC with differential was continued. After 8 days,
including 2 consecutive days of ANC .2,000/mL, clozapine
was restarted at 25 mg daily at bedtime, eventually reaching
the previous maintenance dose of 250 mg twice daily. During
that period, the veteran experienced occasional anxiety and
persistent auditory hallucinations on a daily basis, both male
and female. Voices were derogatory in content, but there
was no evidence of command hallucinations, visual hallu-
cinations, or suicidal ideation. Other medication changes
were made to address current symptoms, including the ad-
dition of divalproex for mood stabilization and seizure
prophylaxis, clonazepam for anxiety, and mirtazapine for
depressive symptoms. Six months later (in October 2014),
the ANC decreased from 2,800/mL to 1,700/mL. Mirtazapine
was discontinued. Further reduction in neutrophil count
persisted despite mirtazapine discontinuation, and cloza-
pine and divalproex were also discontinued 3 days later. The
ANC continued to decrease, and omeprazole was also dis-
continued; haloperidol and olanzapine were trialed for
psychotic symptoms. Lithium was initiated, given data sug-
gesting positive impact on circulating neutrophil counts (8).
However, the decline in ANC persisted, reaching 300/mL
1 week after clozapine was discontinued. Olanzapine and
lithium were discontinued the next day. The veteran re-
ported feeling worried and anxious but, overall, stable. The
hematology staff was consulted and advised to continue to
hold clozapine. Haloperidol was replaced with tri-
fluoperazine per patient preference and then titrated up-
ward to manage psychotic symptoms. Mirtazapine was
restarted for depressive symptoms, and pantoprazole was
initiated for peptic ulcer disease. The ANC and white blood
cell count began to trend upward. However, the veteran then
began to decompensate and was transferred from the long-
term care unit to the acute psychiatry unit because of
worsening paranoia, auditory hallucinations, and thoughts
of self-harm. Within the next 6 months (October 2014–April
2015), he required four separate acute admissions for similar
symptoms, despite a regimen of lurasidone (replacing tri-
fluoperazine), clonazepam, trazodone, olanzapine, lithium,
and hydroxyzine.
CLOZAPINE TRIAL 2 (APRIL 2015–MAY 2015)
In April 2015, it was determined that the veteran would
benefit from retrial of clozapine. Under the guidelines at that
time, he was deemed “non-rechallengeable” (9). However,
there was still evidence to support careful use of the medi-
cation in extenuating circumstances (6). The Department
of Veterans Affairs (VA) allows for a special protocol,
Focus Vol. 19, No. 1, Winter 2021
SHUMAN ET AL.
authorized at a national level. Previous neutropenic episodes
were first reviewed to determine whether polypharmacy
was contributory. Valproic acid and omeprazole were both
identified as potential factors (10–15).
With the aforementioned information, the case was pre-
sented to the VA’s National Clozapine Coordinating Center
(NCCC) and approved using a special protocol. The CBC
was to be assessed thrice weekly for 1 month; if the ANC
remained.1,000/mL, the plan was to decrease monitoring to
twice weekly for 1 month and then weekly thereafter. If the
ANC were to decrease, the plan was to increase monitoring
frequency until again stable. Because of a history of neu-
tropenia likely exacerbated by drug-drug interactions, it was
requested that no new medications be administered to the
veteran without first discussing this with both the psychia-
trist and clinical pharmacist. This was emphasized by plac-
ing a note in the veteran’s chart describing the presence of a
special protocol and restriction on new medications. Addi-
tionally, this document was scanned for patient records.
If the ANC ,1,000/mL, the veteran was to be admitted to
the acute medicine unit and continued on clozapine, re-
ceiving a 6-mg dose of pegfilgrastim. This threshold for the
use of pegfilgrastim was originally set at ,1,500/mL. How-
ever, it was lowered to minimize overall exposure to peg-
filgrastim. This PEGylated formulation of filgrastim was
chosen specifically because of its longer half-life and the
hypothesis that this would allow for sustained protection
against neutropenia (16). A meta-analysis of patients re-
ceiving cyclic doses of pegfilgrastim or daily doses of fil-
grastim for treatment of neutropenia found similar rates of
efficacy between the two agents (17). However, one study
within the meta-analysis found that pegfilgrastim was su-
perior in terms of febrile neutropenia rates. If the ANC were
to fall below 500/mL, the plan was to stop clozapine and not
rechallenge.
This protocol was reviewed nationally and approved.
Clozapine was initiated at 25 mg daily on April 27th and
increased gradually, reaching a dose of 100 mg BID on May
15th. Other psychotropic medications at that time included
40 mg olanzapine daily, 300 mg lithium daily, 0.5 mg lor-
azepam by mouth every 6 hours as needed, 25 mg hy-
droxyzine BID, 0.5 mg benztropine daily, and 100 mg
trazodone at bedtime. On day 22 of clozapine administration,
the ANC began to decrease, reaching 900/mL on day 25. Per
protocol, 6 mg pegfilgrastim was administered that day;
however, the ANC continued to decrease below 500/mL on
day 27. Clozapine was discontinued, and the ANC began to
increase thereafter.
CLOZAPINE TRIAL 3 (DECEMBER 2017–PRESENT)
It was determined that a weakness of the initial protocol in
2015 was the use of “as-needed” doses of pegfilgrastim. Re-
cent literature was noted to discuss preemptive dosing of
filgrastim to prevent neutropenia, a strategy under consid-
eration for this veteran during the previous trial but not
focus.psychiatryonline.org 67
APPLIED ARMAMENTARIUM
FIGURE 1. Absolute neutrophil count (ANC) and filgrastim dose versus time
utilized (18). On the basis of further review of safety of
dosing for as long as 48 months after clozapine initiation,
and a lack of studies explicitly utilizing pegfilgrastim, the
team planned to administer 300 mg filgrastim subcutane-
ously three times weekly, concurrently with clozapine ini-
tiation. Doses were to be adjusted up or down to maintain an
ANC between 2,000/mL and 8,000/mL. Should the ANC
decrease below 1,000/mL, the veteran was to be admitted to
the acute medicine unit, and the hematology team was to be
consulted for additional guidance. This plan was discussed
on both local and national levels to achieve consensus (a
specific protocol is available from the authors on request),
and written informed consent was obtained from the patient
after the treatment protocol had been fully explained to him.
Given the concern for continuity of care should the need
arise to transfer the veteran to a higher or lower level of care,
a chart flag was entered within the electronic health record
apprising all providers of the protocol, including the request
that no new medications be administered without first dis-
cussing with both the psychiatrist and clinical pharmacist.
The protocol itself was also entered into the electronic
health record for review by any provider.
OUTCOME AND FOLLOW-UP
In December 2017, clozapine was successfully initiated with
the aforementioned protocol. Pimavanserin and olanzapine
were eventually discontinued, and the clozapine dose was
titrated to the previous maintenance dose of 250 mg BID;
lithium was added for additional neutrophil stabilization,
68 focus.psychiatryonline.org
and the previous clonazepam regimen was continued. The
veteran continued to report persecutory delusions, refer-
ential delusions, and paranoia regarding his being trans-
ferred off the unit. However, he remained able to complete
activities of daily living, participate in daily yoga, and draw
both for pleasure and to compete in art exhibitions at the
facility. Throughout clozapine treatment, he denied suici-
dality, with no further acute hospitalizations required. On
day 23 of clozapine treatment, the ANC decreased to 900/
mL, and the filgrastim dose was adjusted to maintain the
ANC within the desired range (Figure 1). The frequency of
filgrastim injections and ANC monitoring decreased over
time because of the ANC stabilization. Minor changes were
made to the protocol, given concern for elevated ANC; as a
result, the protocol was modified so that the filgrastim dose
decreased to 300 mg twice weekly and was held if the
ANC .3,000/mL. Lithium was subsequently discontinued,
with no negative impact on neutrophil count. The veteran
has not needed any doses of filgrastim since day 240 of
clozapine treatment. Interestingly, the facility instituted a
smoking ban that occurred after the patient had received
approximately 22 months of clozapine treatment. As a result,
his clozapine level increased from 646 to 1,166 ng/mL before
the dose was adjusted to target a lower maintenance range.
Again, no episodes of neutropenia or seizures were noted.
DISCUSSION
Clozapine is a highly effective antipsychotic and one that is
underutilized within the VA setting (19). One factor that was
Focus Vol. 19, No. 1, Winter 2021

found to influence clozapine utilization was the absence or
presence of a multidisciplinary team to ensure safe and ef-
fective care. Through the involvement of a multidisciplinary
team, the veteran in this case was able to be safely initiated
on clozapine and maintained on a therapeutic dose, with no
ANC excursions below 500/mL, despite 2 years of continu-
ous treatment. However, this case may not be necessarily
applicable to all hospital settings. Although behavioral flags
and those related to patient confidentiality are often used
within the VA setting, this was the first medication-specific
flag to be implemented at our facility. Such a process is time
sensitive and thus requires the support of a clozapine
treatment team.
One other fact to note is that, in our case, the initiation of
lithium did not produce any significant improvement in
neutrophil count, nor did the discontinuation of lithium
decrease the neutrophil count. Clozapine rechallenge has
been shown to be less successful when patients are copre-
scribed both lithium and colony-stimulating factor (CSF),
such as filgrastim (18). This is surprising, as there are multiple
reports of successful use of lithium to treat clozapine-induced
neutropenia, and given the concern for the precipitous drop in
ANC upon its discontinuation (20). Our case demonstrates
that further research may be necessary to quantify the effect
of lithium on increasing ANC in clozapine recipients, partic-
ularly those who are coprescribed CSF.
Myles and colleagues, in a recent meta-analysis, have
provided additional data regarding rates of neutropenia as-
sociated with clozapine use. Assuming a neutropenia
threshold of 1,000/mL, they noted a 1.3% incidence over the
course of the included studies (21). The rate decreased to
0.9% if neutropenia was more tightly defined as an ANC less
than 500/mL, and 89% of neutropenia cases occurred within
the first year of treatment, with the peak incidence occurring
after 1 month. This is similar to the experience with the most
recent clozapine titration (Figure 1). However, our case il-
lustrates that there are still times at which neutropenia may
occur even past this 1-year mark, given that the veteran was
initially maintained on clozapine for many years before ex-
periencing significant neutropenia. These findings are sup-
ported by a similar case, also reported from a VA facility, of a
55-year-old man who developed neutropenia after 20 years
of clozapine therapy. He, too, responded well to filgrastim
coadministration to maintain clozapine treatment (22).
Given that neutropenia may develop because of idio-
pathic reactions as well as drug-drug interactions, continued
monitoring is still warranted throughout treatment with
clozapine. The patient in our case is eligible for less frequent
monitoring of ANC every 4 weeks. After discussion with the
NCCC, the treating providers determined that continuing to
monitor every 2 weeks would allow for more acute man-
agement of neutropenia should it occur again; at that point,
the current protocol would allow for the resumption of fil-
grastim. Myles and colleagues (18) noted that, although
prophylactic administration of filgrastim was the most
common approach to prevent neutropenia on clozapine
Focus Vol. 19, No. 1, Winter 2021
SHUMAN ET AL.
rechallenge, the strategies using “as-required” doses of fil-
grastim were the most successful. Utilizing a prophylactic
strategy initially and then gradually adjusting or holding the
dose to maintain a prespecified ANC range, as was utilized in
this case, may provide a more flexible approach that requires
further exploration. We hope that this case illustrates the
risks and benefits of various strategies of CSF use and may
serve as a potential model for successful clozapine use in the
future, particularly in situations in which neutropenia is of
concern for patients and providers.
AUTHOR AND ARTICLE INFORMATION
Pharmacy Department, Central State Hospital, Louisville, Kentucky
(Shuman); College of Medicine, Rosalind Franklin University of Medicine
and Science, North Chicago (Moss); Pharmacy Department, Captain
James A. Lovell Federal Health Care Center, North Chicago (Dilich).
Send correspondence to Dr. Shuman (michael.shuman@ky.gov).
Sections of this article were previously discussed as a therapeutic case
report presentation at the annual meeting of the College of Psychiatric
and Neurologic Pharmacists, April 7–10, 2019, Salt Lake City.
The authors thank Nicholas Myles, M.B.B.S., for his expertise and assis-
tance regarding this case.
The authors report no financial relationships with commercial interests.
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Perspectives in Psychopharmacology
This section contains a compilation of recent publications that have shaped the thinking in the field as well as classic works
that remain important to the subject reviewed in this issue. This bibliography has been compiled by experts in the field and
members of the editorial and advisory boards. Entries are listed chronologically by first author. Articles from the bibliography
that are reprinted in this issue are in bold type.
2020
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Focus Vol. 19, No. 1, Winter 2021
BIBLIOGRAPHY
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prevalence in the period of second-generation antipsychotic
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randomized, double-blind, placebo-controlled trial of valbenazine
for tardive dyskinesia. Am J Psychiatry 2017; 174:476–484
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(SAGE-547 injection) in post-partum depression: a random-
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Focus Vol. 19, No. 1, Winter 2021

Perspectives in Psychopharmacology
Given space limitations and varying reprint permission policies, not all of the influential publications the editors considered
reprinting in this issue could be included. This section contains abstracts from additional articles the editors deemed well
worth reviewing.
Adjunctive Metformin for Antipsychotic-Induced
Dyslipidemia: A Meta-Analysis of Randomized,
Double-Blind, Placebo-Controlled Trials
Jiang WL, Cai D.B., Yin F, et al.
Transl Psychiatry 2020 Apr 23; 10(1):117
Antipsychotic-induced dyslipidemia could increase the risk
of cardiovascular diseases. This is a meta-analysis of ran-
domized double-blind placebo-controlled trials to examine
the efficacy and safety of adjunctive metformin for dyslipi-
demia induced by antipsychotics in schizophrenia. The
standardized mean differences (SMDs) and risk ratios (RRs)
with their 95% confidence intervals (CIs) were calculated
using the random-effects model with the RevMan 5.3 ver-
sion software. The primary outcome was the change of se-
rum lipid level. Twelve studies with 1215 schizophrenia
patients (592 in metformin group and 623 in placebo group)
were included and analyzed. Adjunctive metformin was
significantly superior to placebo with regards to low density
lipoprotein cholesterol (LDL-C) [SMD: -0.37 (95%CI:-0.69,
-0.05), p50.02; I2 5 78%], total cholesterol [SMD: -0.47
(95%CI:-0.66, -0.29), p,0.00001; I2 5 49%], triglyceride
[SMD: -0.33 (95%CI:-0.45, -0.20), p,0.00001; I2 5 0%], and
high density lipoprotein cholesterol [SMD: 0.29 (95%CI:
0.02, 0.57), p50.03; I2 5 69%]. The superiority of metformin
in improving LDL-C level disappeared in a sensitivity anal-
ysis and 80% (8/10) of subgroup analyses. Metformin was
significantly superior to placebo with regards to decrease in
body weight, body mass index, glycated hemoglobin A1c,
fasting insulin, and homeostasis model assessment-insulin
resistance (p50.002–0.01), but not regarding changes in
waist circumference, waist-to-hip rate, leptin, fasting glu-
cose, and blood pressure (p50.07–0.33). The rates of dis-
continuation due to any reason [RR: 0.97 (95%CI: 0.66, 1.43),
p50.89; I2 5 0%] was similar between the two groups.
Adjunctive metformin could be useful to improve total
cholesterol and triglyceride levels, but it was not effective in
improving LDL-C level in schizophrenia.
Copyright © 2020 Springer Nature
Focus Vol. 19, No. 1, Winter 2021
ABSTRACTS
Novel Antipsychotics Specificity Profile: A
Clinically Oriented Review of Lurasidone,
Brexpiprazole, Cariprazine and Lumateperone
Corponi F, Fabbri C, Bitter I, et al.
Eur Neuropsychopharmacol 2019; 29(9):971–985
Second generation antipsychotics (SGAs) are effective op-
tions in the treatment of schizophrenia and mood disor-
ders, each with characteristic efficacy and safety features.
In order to optimize the balance between efficacy and side
effects, it is of upmost importance to match compound
specificity against patient clinical profile. As the number of
SGAs increased, this review can assist physicians in the
prescription of three novel SGAs already on the market,
namely lurasidone, brexpiprazole, cariprazine, and luma-
teperone, which is in the approval phase for schizophrenia
treatment at the FDA. Besides schizophrenia, EMA and/or
FDA approved lurasidone for bipolar depression, brexpi-
prazole as augmentation in major depressive disorder and
cariprazine for the acute treatment of manic or mixed ep-
isodes associated with bipolar I disorder. These new anti-
psychotics were developed with the aim of improving
efficacy on negative and depressive symptoms and reducing
metabolic and cardiovascular side effects compared with
prior SGAs, while keeping the risk of extrapyramidal
symptoms low. They succeeded quite well in containing
these side effects, despite weight gain during acute treat-
ment remains a possible concern for brexpiprazole, while
cariprazine and lurasidone show higher risk of akathisia
compared with placebo and other SGAs such as olanzapine.
The available studies support the expected benefits on
negative symptoms, cognitive dysfunction and depressive
symptoms, while the overall effect on acute psychotic
symptoms may be similar to other SGAs such as quetiapine,
aripiprazole and ziprasidone. The discussed new antipsy-
chotics represent useful therapeutic options but their ef-
ficacy and side effect profiles should be considered to
personalize prescription.
Copyright © 2019 Elsevier and ECNP. All rights reserved.
focus.psychiatryonline.org 73
ABSTRACTS
Recent Developments in Drug-Induced Movement
Disorders: A Mixed Picture
Factor SA, Burkhard PR, Caroff S, et al.
Lancet Neurol 2019; 18(9):880–890
A large and ever-growing number of medications can induce
various movement disorders. Drug-induced movement disor-
ders are disabling but are often under-recognized and in-
appropriately managed. In particular, second generation
antipsychotics, like first generation agents, are associated
with potentially debilitating side-effects, most notably tardive
syndromes and parkinsonism, as well as potentially fatal acute
syndromes. Appropriate, evidence-based management is essen-
tial as these drugs are being prescribed to a growing population
vulnerable to these side-effects, including children and elderly
people. Prevention of the development of drug-induced move-
ment disorders is an important consideration when prescribing
medications that can induce movement disorders. Recent de-
velopments in diagnosis, such as the use of dopamine transporter
imaging for drug-induced parkinsonism, and treatment, with the
approval of valbenazine and deutetrabenazine, the first drugs
indicated for tardive syndromes, have improved outcomes for
many patients with drug-induced movement disorders. Future
research should focus on development of safer antipsychotics
and specific therapies for the different tardive syndromes and
the treatment of drug-induced parkinsonism.
Copyright © 2019 Elsevier Ltd.
Comparative Efficacy and Tolerability of
Medications for Attention-Deficit Hyperactivity
Disorder in Children, Adolescents, and Adults: A
Systematic Review and Network Meta-Analysis
Cortese S, Adamo N, Del Giovane C, et al.
Lancet Psychiatry 2018; 5(9):727–738
BACKGROUND: The benefits and safety of medications for
attention-deficit hyperactivity disorder (ADHD) remain con-
troversial, and guidelines are inconsistent on which medica-
tions are preferred across different age groups. We aimed to
estimate the comparative efficacy and tolerability of oral
medications for ADHD in children, adolescents, and adults.
METHODS: We did a literature search for published and
unpublished double-blind randomized controlled trials com-
paring amphetamines (including lisdexamfetamine), atom-
oxetine, bupropion, clonidine, guanfacine, methylphenidate,
and modafinil with each other or placebo. We systematically
contacted study authors and drug manufacturers for additional
information. Primary outcomes were efficacy (change in se-
verity of ADHD core symptoms based on teachers’ and clini-
cians’ ratings) and tolerability (proportion of patients who
dropped out of studies because of side-effects) at timepoints
closest to 12 weeks, 26 weeks, and 52 weeks. We estimated
summary odds ratios (ORs) and standardized mean differences
(SMDs) using pairwise and network meta-analysis with random
effects. We assessed the risk of bias of individual studies with
74 focus.psychiatryonline.org
the Cochrane risk of bias tool and confidence of estimates with
the Grading of Recommendations Assessment, Development,
and Evaluation approach for network meta-analyses. This study
is registered with PROSPERO, number CRD42014008976.
FINDINGS: 133 double-blind randomized controlled trials
(81 in children and adolescents, 51 in adults, and one in both)
were included. The analysis of efficacy closest to 12 weeks was
based on 10 068 children and adolescents and 8131 adults; the
analysis of tolerability was based on 11 018 children and ado-
lescents and 5362 adults. The confidence of estimates varied
from high or moderate (for some comparisons) to low or very
low (for most indirect comparisons). For ADHD core symp-
toms rated by clinicians in children and adolescents closest to
12 weeks, all included drugs were superior to placebo (e.g.
SMD -1·02, 95% CI -1·19 to -0·85 for amphetamines, -0·78,
-0·93 to -0·62 for methylphenidate, -0·56, -0·66 to -0·45 for
atomoxetine). By contrast, for available comparisons based on
teachers’ ratings, only methylphenidate (SMD -0·82, 95% CI
-1·16 to -0·48) and modafinil (20·76, -1·15 to -0·37) were more
efficacious than placebo. In adults (clinicians’ ratings), am-
phetamines (SMD -0·79, 95% CI -0·99 to -0·58), methylphe-
nidate (20·49, -0·64 to -0·35), bupropion (20·46, -0·85 to
-0·07), and atomoxetine (20·45, -0·58 to -0·32), but not
modafinil (0·16, -0·28 to 0·59), were better than placebo. With
respect to tolerability, amphetamines were inferior to placebo
in both children and adolescents (odds ratio [OR] 2·30, 95% CI
1·36–3·89) and adults (3·26, 1·54–6·92); guanfacine was inferior
to placebo in children and adolescents only (2·64, 1·20–5·81);
and atomoxetine (2·33, 1·28–4·25), methylphenidate (2·39,
1·40–4·08), and modafinil (4·01, 1·42–11·33) were less well
tolerated than placebo in adults only. In head-to-head com-
parisons, only differences in efficacy (clinicians’ ratings) were
found, favoring amphetamines over modafinil, atomoxetine,
and methylphenidate in both children and adolescents (SMDs
-0·46 to -0·24) and adults (20·94 to -0·29). We did not find
sufficient data for the 26-week and 52-week timepoints.
INTERPRETATION: Our findings represent the most
comprehensive available evidence base to inform patients, fam-
ilies, clinicians, guideline developers, and policymakers on the
choice of ADHD medications across age groups. Taking into
account both efficacy and safety, evidence from this meta-analysis
supports methylphenidate in children and adolescents, and am-
phetamines in adults, as preferred first-choice medications for
the short-term treatment of ADHD. New research should be
funded urgently to assess long-term effects of these drugs.
Copyright © 2018 The Author(s). Published by Elsevier Ltd.
Risks and Benefits of Attention-Deficit/
Hyperactivity Disorder Medication on Behavioral
and Neuropsychiatric Outcomes: A Qualitative
Review of Pharmacoepidemiology Studies Using
Linked Prescription Databases
Chang Z, Ghirardi L, Quinn PD, et al.
Biol Psychiatry 2019; 86(5):335–343
Focus Vol. 19, No. 1, Winter 2021

Attention-deficit/hyperactivity disorder (ADHD) medication
is one of the most commonly prescribed medication classes in
child and adolescent psychiatry, and its use is increasing rap-
idly in adult psychiatry. However, major questions and con-
cerns remain regarding the benefits and risks of ADHD
medication, especially in real-world settings. We conducted a
qualitative systematic review of studies that investigated the
effects of ADHD medication on behavioral and neuropsychi-
atric outcomes using linked prescription databases from the
last 10 years and identified 40 studies from Europe, North
America, and Asia. Among them, 18 used within-individual
designs to account for confounding by indication. These
studies suggested short-term beneficial effects of ADHD
medication on several behavioral or neuropsychiatric out-
comes (i.e. injuries, motor vehicle accidents, education, sub-
stance use disorder), with estimates suggesting relative risk
reduction of 9% to 58% for these outcomes. The within-
individual studies found no evidence of increased risks for
suicidality and seizures. Replication studies are needed for
several other important outcomes (i.e. criminality, depression,
mania, psychosis). The available evidence from pharmacoe-
pidemiology studies on long-term effects of ADHD medication
was less clear. We discuss time-varying confounding and other
limitations that should be considered when interpreting re-
sults from pharmacoepidemiology studies. Furthermore,
we highlight several knowledge gaps to be addressed in
future research and implications for research on mech-
anisms of outcomes of ADHD medications.
Copyright © 2019 Society of Biological Psychiatry
KINECT 3: A Phase 3 Randomized, Double-Blind,
Placebo-Controlled Trial of Valbenazine for
Tardive Dyskinesia
Hauser RA, Factor SA, Marder SR, et al.
Am J Psychiatry 2017; 174(5):476–484
OBJECTIVE: Tardive dyskinesia is a persistent movement
disorder induced by dopamine receptor blockers, including
Focus Vol. 19, No. 1, Winter 2021
ABSTRACTS
antipsychotics. Valbenazine (NBI-98854) is a novel, highly
selective vesicular monoamine transporter 2 inhibitor that
demonstrated favorable efficacy and tolerability in the
treatment of tardive dyskinesia in phase 2 studies. This
phase 3 study further evaluated the efficacy, safety, and
tolerability of valbenazine as a treatment for tardive
dyskinesia.
METHOD: This 6-week, randomized, double-blind, placebo-
controlled trial included patients with schizophrenia,
schizoaffective disorder, or a mood disorder who had
moderate or severe tardive dyskinesia. Participants were
randomly assigned in a 1:1:1 ratio to once-daily placebo,
valbenazine at 40 mg/day, or valbenazine at 80 mg/day. The
primary efficacy endpoint was change from baseline to week
6 in the 80 mg/day group compared with the placebo group
on the Abnormal Involuntary Movement Scale (AIMS)
dyskinesia score (items 1–7), as assessed by blinded central
AIMS video raters. Safety assessments included adverse
event monitoring, laboratory tests, ECG, and psychiatric
measures.
RESULTS: The intent-to-treat population included 225
participants, of whom 205 completed the study. Approxi-
mately 65% of participants had schizophrenia or schizo-
affective disorder, and 85.5% were receiving concomitant
antipsychotics. Least squares mean change from baseline to
week 6 in AIMS dyskinesia score was -3.2 for the 80 mg/
day group, compared with -0.1 for the placebo group, a
significant difference. AIMS dyskinesia score was also re-
duced in the 40 mg/day group (21.9 compared with -0.1).
The incidence of adverse events was consistent with pre-
vious studies.
CONCLUSIONS: Once-daily valbenazine significantly im-
proved tardive dyskinesia in participants with underlying
schizophrenia, schizoaffective disorder, or mood disorder.
Valbenazine was generally well tolerated, and psychiatric
status remained stable. Longer trials are necessary to un-
derstand the long-term effects of valbenazine in patients
with tardive dyskinesia.
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