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Exploring psychotherapeutic issues and agents in clinical practice
© 2009/Digital Juice, Inc.
Robert H. Howland, MD, Section Editor
Clinical Implications of
Chirality and Stereochemistry
in Psychopharmacology
Chirality, the concept of nonsuperimposable
mirror images, is a fundamental property of
biological systems and can be observed on
a molecular, cellular, or organism level. Stereoisomer compounds possess the same molecular and structural formula, but they differ in their three-dimensional configurations.
Chiral compounds have two mirror-image
stereoisomer forms called enantiomers. Com-
pounds containing mirror-image enantiomers in equal proportions are referred to as
racemic mixtures or racemates. Racemates and
their individual enantiomers can have very
different pharmacological properties that
are relevant in clinical psychopharmacology.
Various examples of drug therapies that show
the clinical importance of chirality and stereochemistry are described.
Robert H. Howland, MD
Journal of Psychosocial Nursing • Vol. 47, No. 8, 2009
“Now, if you’ll only attend, Kitty, and not talk so much, I’ll tell you
all my ideas about Looking-glass House. First, there’s the room you can
see through the glass—that’s just the same as our drawing-room, only the
things go the other way.... The books are something like our books, only
the words go the wrong way…. How would you like to live in the Lookingglass House, Kitty? I wonder if they’d give you milk in there? Perhaps
Looking-glass milk isn’t good to drink.” (Carroll, 1897, pp. 20, 22)
hirality, the concept of
nonsuperimposable mirror images, is a fundamental property of biological
systems and reflects the underlying asymmetry of matter (Cintas,
2007). Indeed, chirality can be
discerned on a molecular, cellular, or organism level (Levin
& Mercola, 1998). For example,
mirror-image twinning occurs in
approximately 10% to 15% of
monozygotic (identical) twins
(Hall, 2003). These twins exhibit
features that are mirror-image opposite each other, such as handedness, hair whorl direction,
tooth patterns, and unilateral
eye and ear defects. Stereoisomer
compounds possess the same molecular and structural formula but
have different three-dimensional
configurations. Chiral compounds have two mirror-image
stereoisomers called enantiomers.
Compounds containing mirrorimage enantiomers in equal proportions are referred to as racemic
mixtures or racemates. Last month,
I described the main principles
of chirality and stereochemistry,
which are essential for understanding the three-dimensional
aspects of psychopharmacology.
In this article, I will review examples of drug therapies in which
chirality and stereochemistry are
clinically relevant.
Antidepressant Drugs
Most antidepressant drugs exist as racemic mixtures and are
marketed in this form, but several
are sold as specific enantiomers
(Baumann & Eap, 2001). For example, the chemical sertraline is
a cis-(1S,4S) enantiomer that was
first marketed as the brand-name
product Zoloft®. Similarly, the
chemical paroxetine is a trans-(–)
enantiomer that was first marketed under the brand name Paxil®.
Selegiline (l-deprenyl; Eldepryl®,
Emsam®), an approved drug for
Parkinson’s disease and depression,
is a phenylalkylamine compound
that structurally resembles amphetamine. The marketed levorotatory enantiomer (l-deprenyl)
is much more biologically active
as a monoamine oxidase enzyme
inhibitor compared with the dextrorotatory enantiomer (Yasar et
al., 2006).
Citalopram (Celexa®) is a
racemic mixture. The pharmacological activity of citalopram (serotonin reuptake inhibition) is mostly attributable
to the S-enantiomer, and the
R-enantiomer may competitively
interfere with this effect (Sánchez, Bøgesø, Ebert, Reines, &
Braestrup, 2004). For this reason,
the S-enantiomer escitalopram
(Lexapro®) was further developed as an antidepressant drug.
Fluoxetine (Prozac®) is a
racemate. The R-fluoxetine and
S-fluoxetine enantiomers have
differential effects on neurotransmitter transporters, liver metabolic enzymes, and cardiac function.
The development of R-fluoxetine
as a more “pure” antidepressant
molecule was halted because of
increased adverse cardiac effects
(Shah, 2002), whereas further
development of S-fluoxetine as a
treatment for migraine headaches
has had mixed results (Steiner,
Ahmed, Findley, MacGregor, &
Wilkinson, 1998).
Stimulant and
(Focalin®) is the d-enantiomer of
the racemate stimulant drug methylphenidate (Ritalin®). Preclinical studies have shown that the
d-enantiomer accounts for most
of the biological activity of the
racemate methylphenidate (Heal
& Pierce, 2006). Clinical studies
suggest that dexmethylphenidate
has similar or slightly greater efficacy than methylphenidate in
disorder (ADHD), with a lower
propensity for adverse effects and
can be given in half the dosage of
racemic methylphenidate.
Amphetamine products are
available as dextroamphetamine
(Adderall®), and lisdexamfetamine
(Vyvanse®). Dextroamphetamine
is the d-enantiomer of the racemate drug amphetamine (Patrick
& Markowitz, 1997). Dextroamphetamine and levoamphetamine
have differential effects on the
neurotransmitters dopamine and
norepinephrine and on the metabolic enzyme monoamine oxidase,
and their pharmacokinetic profiles are somewhat different. Early
studies suggested that both drugs
were effective overall for treating
ADHD, but they appeared to have
differential effects on attention
and hyperactivity. Levoamphetamine is not marketed separately
but is present in small amounts in
the amphetamine/dextroamphetamine combination products.
Prodrugs are pharmacologically inactive compounds that are
converted to biologically active
metabolites. Lisdexamfetamine is
an inactive prodrug in which the
enantiomer dextroamphetamine
is chemically bonded to the
amino acid enantiomer L-lysine
(Howland, 2008). After oral ingestion, the bond is metabolically
cleaved in the gut, and lisdexamfetamine is converted to L-lysine
and to the pharmacologically active drug dextroamphetamine.
Compared with regular orally
exposure to dextroamphetamine
that is released from lisdexamfetamine is decreased and delayed
in an extended-release pattern.
Pseudoephedrine (Sudafed®),
approved for nasal sinus congestion, is the dextro-enantiomer
form of the racemate ephedrine
(Mistole®), which is approved
for nasal congestion and acute
bronchospasm. It is approximately one fourth as potent as ephedrine as a sympathomimetic agent,
with much fewer adverse cardiovascular effects (Drew, Knight,
Hughes, & Bush, 1978).
Modafinil (Provigil®) is a racemic stimulant-like drug (unrelated to methylphenidate or
amphetamine). It is approved
for the treatment of excessive
daytime sleepiness associated
with narcolepsy, sleep apnea,
and shift work sleep disorder.
The R-modafinil enantiomer has
a half-life that is significantly
longer than that of S-modafinil,
and the elimination of Smodafinil is about three times
faster than R-modafinil (Wisor,
Dement, Aimone, Williams, &
Bozyczko-Coyne, 2006). Because
R-modafinil is expected to have
a longer daytime therapeutic effect than racemic modafinil, the
R-modafinil enantiomer (Nuvigil®) has been approved for
the same indications as racemic
Other Drugs
Thalidomide (Thalomid®) was
originally developed and marketed in the 1950s as a sedative
medication for treating morning
sickness during pregnancy. It was
subsequently withdrawn when
found to be associated with significant birth defects but was later reintroduced for treating other
medical conditions. Thalidomide
exists as a racemic mixture of Rand S- enantiomers. Studies have
shown that the S-thalidomide
in Parkinson’s disease found that
the most significant side effects of
the drug were attributable to the
D-dopa enantiomer (Coutts &
Baker, 1989).
Esomeprazole (Nexium®), a
proton pump inhibitor used to
suppress gastric acid secretion,
is the S-enantiomer of the racemate omeprazole (Prilosec®). The
drugs have different pharmacokinetic properties: Esomeprazole
has less first-pass hepatic metabolism, a lower plasma clearance,
Most antidepressant drugs exist as racemic mixtures and are
marketed in this form, but several are sold as specific
enantiomer may have been selectively responsible for the birth
defects associated with use of
thalidomide (Waldeck, 2003).
The thyroid hormone thyroxine exists as a racemic mixture of
levothyroxine (L-thyroxine) and
dextrothyroxine (D-thyroxine).
Levothyroxine (Levoxyl®, Synthroid®) is used as replacement
therapy for hypothyroidism.
Dextrothyroxine (Choloxin®)
is much less potent than levothyroxine. It is approved for the
treatment of hypercholesterolemia but is no longer commercially available. The drug was
associated with a significantly
higher rate of cardiovascular
mortality in clinical trials, and
the manufacturer ceased production (Denke, 2005).
Dopa is an amino acid precursor of the neurotransmitter
dopamine, and it exists as a racemic mixture of the enantiomers
levodopa (L-dopa) and dextrodopa (D-dopa). Levodopa is used
for the treatment of Parkinson’s
disease. The early studies of dopa
Journal of Psychosocial Nursing • Vol. 47, No. 8, 2009
and greater oral bioavailability compared
with omeprazole (Dent, 2003).
Pregabalin (Lyrica®) is a
chemical analog of the inhibitory
amino acid gamma-aminobutyric
acid (GABA). It is approved for
the treatment of diabetic neuropathy and fibromyalgia. Pregabalin is the pharmacologically
active S-enantiomer of racemic
3-isobutyl GABA (Frampton &
Foster, 2006). Compared with the
racemate, pregabalin binds with
higher affinity to a particular site
of the GABA receptor complex
in the central nervous system.
is a marketed hypnotic agent
(Lunesta®) for insomnia. It is the
S-enantiomer of racemic zopiclone (Imovane®), which is not
available in the United States
but is marketed elsewhere for the
treatment of insomnia. Preclinical trials demonstrated that the
S-enantiomer was more active
at the benzodiazepine receptor
complex than the R-enantiomer
and contributed to most of the
hypnotic activity of racemic zopiclone (Lane & Baker, 1999).
Ketamine (Ketolar®), an anesthetic agent derived from the
hallucinogenic drug phencyclidine (PCP), is a racemate that
has been investigated for treatment-resistant depression. Compared with racemate ketamine,
the S-ketamine enantiomer is
less likely to cause perceptual
disturbances and confusion,
while preserving its anesthetic
has little or no analgesic activity (Burke & Kratochvil, 2002).
Although no longer manufactured, the levopropoxyphene
enantiomer was once marketed
as a centrally acting cough suppressant with the trade name
Novrad® (Darvon spelled backward).
Alice wondered whether
Looking-glass milk might not
Profound differences can sometimes be
demonstrated between different chemical
and potential antidepressant effects (Burke & Henderson, 2002;
Paul, Schaaff, Padberg, Moller, &
Frodl, 2007).
Methadone (Dolophine®), a
synthetic opioid analgesic, is a
racemate. The R-methadone enantiomer is more pharmacologically active and potent than
S-methadone. The metabolism
of racemate methadone in the
liver is stereospecific, which
means that each enantiomer is
metabolized differently by various hepatic enzymes. Taking
medications that selectively inhibit the metabolic enzyme that
the R-methadone enantiomer
may increase R-methadone concentrations, potentially resulting
in greater analgesic and adverse
effects (Uehlinger et al., 2007).
Propoxyphene, an opioid
analgesic structurally related
to methadone, exists as a racemate. The dextropropoxyphene
enantiomer is marketed as an
analgesic (Darvon®) because the
levopropoxyphene enantiomer
be good to drink. If one considers the chemical constituents
of milk, it would certainly be
reasonable to speculate about
the possible physiological differences in mirror-image milk.
Odors and tastes are chemically
mediated, and profound differences can sometimes be demonstrated between different chemical enantiomers (Sell, 2004;
Temussi, 2009). For example,
the dipeptide combination of
the amino acids L-aspartic acid
and L-phenyl-alanine methyl
ester (L-Asp-L-PheOMe) is
manufactured as the artificial
sweetener aspartame. However,
this dipeptide combination can
exist in four stereoisomer forms.
The stereoisomers D-Asp-DPheOMe, D-Asp-L-PheOMe,
and L-Asp-D-PheOMe are bitter. Because the introduction
of stereochemically pure drugs
is expected to increase, nurses
should understand the rationale
for their development and how
they may improve the pharmacotherapy of patient care.
Baumann, P., & Eap, C.B. (2001). Enantiomeric antidepressant drugs should
be considered on individual merit.
Human Psychopharmacology: Clinical
and Experimental, 16(Suppl. 2), S85S92.
Burke, D., & Henderson, D.J. (2002).
Chirality: A blueprint for the future.
British Journal of Anaesthesia, 88, 563576.
Burke, W.J., & Kratochvil, C.J. (2002).
Stereoisomers in psychiatry: The case
of escitalopram. Primary Care Companion to the Journal of Clinical Psychiatry, 4, 20-24.
Carroll, L. (1897). Through the lookingglass, and what Alice found there. Philadelphia: Henry Altemus.
Cintas, P. (2007). Tracing the origins and
evolution of chirality and handedness
in chemical language. Angewandte
Chemie International Edition, 46,
Coutts, R.T., & Baker, G.B. (1989). Implications of chirality and geometric
isomerism in some psychoactive drugs
and their metabolites. Chirality, 1,
Denke, M.A. (2005). Diet, lifestyle, and
nonstatin trials: Review of time to
benefit. American Journal of Cardiology, 96(5A), 3F-10F.
Dent, J. (2003). Review article: Pharmacology of esomeprazole and comparisons with omeprazole. Alimentary Pharmacology and Therapeutics,
17(Suppl. 1), 5-9.
Drew, C.D., Knight, G.T., Hughes, D.T.,
& Bush, M. (1978). Comparison of
the effects of D-(-)-ephedrine and
L-(+)-pseudoephedrine on the cardiovascular and respiratory systems in
man. British Journal of Clinical Pharmacology, 6, 221-225.
Frampton, J.E., & Foster, R.H. (2006).
Pregabalin: In the treatment of generalized anxiety disorder. CNS Drugs,
20, 685-693.
Hall, J.G. (2003). Twinning. Lancet, 362,
Heal, D.J., & Pierce, D.M. (2006). Methylphenidate and its isomers: Their
role in the treatment of attentiondeficit hyperactivity disorder using
a transdermal delivery system. CNS
Drugs, 20, 713-738.
Howland, R.H. (2008). Lisdexamfetamine:
A prodrug stimulant for ADHD. Journal of Psychosocial Nursing and Mental
Health Services, 46(8), 19-22.
Lane, R.M., & Baker, G.B. (1999). Chirality and drugs used in psychiatry:
Nice to know or need to know? Cellular and Molecular Neurobiology, 19,
Levin, M., & Mercola, M. (1998). The
compulsion of chirality: Toward an
understanding of left-right asymmetry. Genes and Development, 12, 763769.
Patrick, K.S., & Markowitz, J.S. (1997).
Pharmacology of methylphenidate,
amphetamine enantiomers and
pemoline in attention-deficit hyperactivity disorder. Human Psychopharmacology: Clinical and Experimental,
12, 527-546.
Paul, R., Schaaff, N., Padberg, F., Moller,
H.J., & Frodl, T. (2007). Comparison
of racemic ketamine and S-ketamine
in treatment-resistant depression: Report of two cases. World Journal of Biological Psychiatry. First published online
October 29, 2007. doi: 10.1080/15622
Sánchez, C., Bøgesø, K.P., Ebert, B.,
Reines, E.H., & Braestrup, C. (2004).
Escitalopram versus citalopram: The
surprising role of the R-enantiomer.
Psychopharmacology, 174, 163-176.
Sell, C.S. (2004). Scent through the looking glass. Chemistry and Biodiversity, 1,
Shah, R.R. (2002). The significance of
QT interval in drug development.
British Journal of Clinical Pharmacology, 54, 188-202.
Steiner, T.J., Ahmed, F., Findley, L.J.,
MacGregor, E.A., & Wilkinson, M.
(1998). S-fluoxetine in the prophylaxis of migraine: A phase II doubleblind randomized placebo-controlled
study. Cephalalgia, 18, 283-286.
Temussi, P.A. (2009). Sweet, bitter and
umami receptors: A complex relationship. Trends in Biochemical Sciences, 34, 296-302.
Uehlinger, C., Crettol, S., Chassot, P.,
Brocard, M., Koeb, L., BrawandAmey, M., et al. (2007). Increased
(R)-methadone plasma concentrations by quetiapine in cytrochrome
P450s and ABCB1 genotyped patients. Journal of Clinical Psychopharmacology, 27, 273-278.
Waldeck, B. (2003). Three-dimensional
pharmacology, a subject ranging
from ignorance to overstatements.
Pharmacology and Toxicology, 93,
Wisor, J.P., Dement, W.C., Aimone, L.,
Williams, M., & Bozyczko-Coyne, D.
(2006). Armodafinil, the R-enantiomer of modafinil: Wake-promoting
effects and pharmacokinetic profile
in the rat. Pharmacology, Biochemistry, and Behavior, 85, 492-499.
Yasar, S., Gaál, J., Panlilio, L.V., Justinova, Z., Molnár, S.V., Redhi, G.H.,
et al. (2006). A comparison of drugseeking behavior maintained by
D-amphetamine, L-deprenyl (selegiline), and D-deprenyl under a secondorder schedule in squirrel monkeys.
Psychopharmacology, 183, 413-421.
Dr. Howland is Associate Professor
of Psychiatry, University of Pittsburgh
School of Medicine, Western Psychiatric
Institute and Clinic, Pittsburgh, Pennsylvania.
The author discloses that he has
no significant financial interests in any
product or class of products discussed
directly or indirectly in this activity,
including research support.
Address correspondence to Robert
H. Howland, MD, Associate Professor
of Psychiatry, University of Pittsburgh
School of Medicine, Western Psychiatric
Institute and Clinic, 3811 O’Hara
Street, Pittsburgh, PA 15213; e-mail:
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