Medication used for major depressive disorder
Gepirone , sold under the brand name Exxua , is a
medication used for the treatment of
major depressive disorder .
[1] It is taken
orally .
[1]
Side effects of gepirone include
dizziness ,
nausea ,
insomnia ,
abdominal pain , and
dyspepsia (indigestion).
[1] Gepirone acts as a
partial agonist of the
serotonin
5-HT1A receptor .
[1]
[2] An
active metabolite of gepirone,
1-(2-pyrimidinyl)piperazine , is an
α2 -adrenergic receptor
antagonist .
[1]
[3] Gepirone is a member of the
azapirone group of compounds.
[2]
Gepirone was synthesized by
Bristol-Myers Squibb in 1986 and was developed and marketed by
Fabre-Kramer Pharmaceuticals .
[4] It was approved for the treatment of major depressive disorder in the United States in September 2023.
[4] This came after the drug had been rejected by the
Food and Drug Administration three times over two decades due to insufficient evidence of effectiveness.
[5]
Medical uses
Gepirone is
indicated for the treatment of
major depressive disorder in adults.
[1] Of 15 clinical trials of gepirone for major depressive disorder submitted to the United States
Food and Drug Administration (FDA), three were excluded for
methodological reasons, three were deemed "failed" and "uninformative", seven were deemed negative and did not demonstrate effectiveness, and two were deemed positive and did show effectiveness.
[6] Two positive trials are needed for FDA drug approval, with this being the case regardless of the number of negative trials.
[7] In the two positive trials of gepirone for depression, the drug
significantly outperformed
placebo in terms of depressive symptom reduction and showed
effect sizes similar to those of other approved antidepressants.
[1]
[8] In both trials, gepirone reduced depressive symptoms by about 2.5 points more than placebo on the 52-point
Hamilton Depression Rating Scale (17-item version or HAMD-17).
[1] The baseline depression scores in the trials ranged from 22.7 to 24.2 in the different patient groups.
[1]
Available forms
Gepirone comes in the form of
extended-release
tablets of the
hydrochloride
salt , gepirone hydrochloride, in the strengths 18.2 mg, 36.3 mg, 54.5 mg, and 72.6 mg.
[1]
Specific populations
It is not known if gepirone is safe in women who are breastfeeding. Medications with more data in this setting may be preferred.
[9]
Contraindications
Gepirone is
contraindicated in people that have experienced an allergic reaction to gepirone, a corrected
QT interval > 450 msec, a history of congenital
long QT syndrome , use medications that strongly inhibit CYP3A4 (an enzyme involved in gepirone's metabolism), severe liver problems, or have used a
monoamine oxidase inhibitor medication within 14 days.
[1]
Side effects
Serious
side effects of gepirone include
QT prolongation (increases the risk of a potentially life-threatening cardiac arrhythmia called
torsade de pointes ),
serotonin syndrome (especially in the presence of other serotonergic drugs), and activation of
mania or hypomania in people with
bipolar disorder . Common side effects include dizziness, nausea, insomnia, abdominal pain, and dyspepsia (indigestion).
[1]
Interactions
The
CYP3A4
inhibitors
ketoconazole and
verapamil strongly increase exposure to gepirone, whereas
lithium ,
paroxetine , and
warfarin have no effect on exposure to gepirone.
[1] The CYP3A4
inducer
rifampin profoundly decreases exposure to gepirone.
[1]
Pharmacology
Pharmacodynamics
Gepirone acts as a
selective
partial agonist of the
5-HT1A receptor .
[2] Unlike its relative
buspirone , however, gepirone has greater
efficacy in activating the 5-HT1A and has negligible
affinity for the
D2 receptor (30- to 50-fold lower in comparison to
buspirone ).
[10] However, similarly to buspirone, gepirone
metabolizes into
1-(2-pyrimidinyl)piperazine (1-PP), which is known to act as a
potent
antagonist of the
α2 -adrenergic receptor .
[3]
Pharmacokinetics
Absorption
The
absolute bioavailability of gepirone is 14 to 17%.
[1] The
time to peak concentrations of gepirone with the extended-release formulation is 6 hours.
[1] When taken with a high-fat meal, the time to peak levels decreases to 3 hours.
[1] A high-fat meal increases exposure to gepirone, with the effect increasing dependent on the amount of fat in the meal.
[1]
Peak concentrations were increased by 27% with a low-fat meal, 55% with a medium-fat meal, and 62% with a high-fat meal, while
area-under-the-curve levels of gepirone were increased by 14% with a low-fat meal, 22% with a medium-fat meal, and 32 to 37% with a high-fat meal.
[1] The effect was similar for the
metabolites of gepirone, 1-PP and 3'-hydroxygepirone (3'-OH-gepirone).
[1]
Distribution
The apparent
volume of distribution of gepirone is approximately 94.5 L.
[1] The
plasma protein binding of gepirone
in vitro is 72% and is independent of concentration.
[1] The plasma protein binding of 3'-OH-gepirone is 59% and of 1-PP is 42%.
[1]
Metabolism
Gepirone is
metabolized primarily by
CYP3A4 .
[1] Its major metabolites are 1-PP and 3'-OH-gepirone, both of which are
pharmacologically active .
[1] These metabolites are present in the circulation at higher concentrations than gepirone.
[1]
Elimination
With a single oral dose of
radiolabeled gepirone, 81% is recovered in
urine and 13% is recovered in
feces as
metabolites .
[1] About 60% of the gepirone is eliminated in urine within 24 hours.
[1]
The
terminal half-life of gepirone as the extended-release form is approximately 5 hours.
[1]
Chemistry
Gepirone is a member of the
azapirone group of compounds and is
structurally related to
buspirone ,
tandospirone , and other azapirones.
[11]
History
Gepirone was
developed by Bristol-Myers Squibb in 1986,
[5] but was out-licensed to
Fabre-Kramer in 1993. The FDA rejected approval for gepirone in 2002 and 2004.
[5] It was submitted for the preregistration (NDA) phase again in May 2007 after adding additional information from clinical trials as the FDA required in 2009. However, in 2012 it once again failed to convince the FDA of its qualities for treating anxiety and depression.
[5] In December 2015, the FDA once again gave gepirone a negative review for depression due to concerns of efficacy.
[12] However, in March 2016, the FDA reversed its decision and gave gepirone ER a positive review.
[13] Gepirone ER was finally approved for the treatment of major depressive disorder in the United States in September 2023.
[5]
Society and culture
Names
The brand name of gepirone is Exxua.
[1] Former tentative brand names which were never used included Ariza, Variza, and Travivo.
[4]
Research
Gepirone is under development for the treatment of
decreased libido and
generalized anxiety disorder .
[4]
[14]
[15] As of October 2023, it is in
phase 3
clinical trials for these indications.
[4] The
pro-sexual effects of gepirone appear to be independent of its antidepressant and anxiolytic effects.
[14]
[15]
References
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"EXXUA (gepirone) extended-release tablets, for oral use" (PDF) . Mission Pharmacal Company . U.S. Food and Drug Administration. 2023.
Archived (PDF) from the original on 28 September 2023. Retrieved 28 September 2023 .
^
a
b
c Kishi T, Meltzer HY, Matsuda Y, Iwata N (August 2014).
"Azapirone 5-HT1A receptor partial agonist treatment for major depressive disorder: systematic review and meta-analysis" (PDF) . Psychological Medicine . 44 (11): 2255–2269.
doi :
10.1017/S0033291713002857 .
PMID
24262766 .
S2CID
20830020 . Archived from
the original (PDF) on 18 February 2019.
^
a
b Halbreich U, Montgomery SA (1 November 2008).
Pharmacotherapy for Mood, Anxiety, and Cognitive Disorders . American Psychiatric Pub. pp. 375–.
ISBN
978-1-58562-821-6 .
^
a
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e
"Gepirone - Fabre-Kramer Pharmaceuticals" . AdisInsight . Springer Nature Switzerland AG.
Archived from the original on 11 April 2023. Retrieved 28 September 2023 .
^
a
b
c
d
e Becker Z (28 September 2023).
"Decades long regulatory odyssey ends with FDA nod for Fabre-Kramer's depression med Exxua" . Fierce Pharma .
^ Firth S (30 November 2015).
"Controversial Antidepressant Comes Up for FDA OK -- Again" . MedPage Today .
^ Kirsch I (2014).
"Antidepressants and the Placebo Effect" . Zeitschrift für Psychologie . 222 (3): 128–134.
doi :
10.1027/2151-2604/a000176 .
PMC
4172306 .
PMID
25279271 .
^
"FDA Rules Favorably On Efficacy Of Travivo (Gepirone ER) For Treatment Of Major Depressive Disorder" . Fabre-Kramer Pharmaceuticals, Inc . Cision PR Newswire. 17 March 2016.
^
"Gepirone" . Drugs and Lactation Database . National Institute of Child Health and Human Development. 2006.
PMID
37856644 . Retrieved 11 December 2023 .
^ Schatzberg AF, Nemeroff CB (2009).
The American Psychiatric Publishing Textbook of Psychopharmacology . American Psychiatric Pub. pp. 494–.
ISBN
978-1-58562-309-9 .
^ Kaur Gill A, Bansal Y, Bhandari R, Kaur S, Kaur J, Singh R, et al. (July 2019). "Gepirone hydrochloride: a novel antidepressant with 5-HT1A agonistic properties". Drugs of Today . 55 (7): 423–437.
doi :
10.1358/dot.2019.55.7.2958474 .
PMID
31347611 .
S2CID
198911377 .
^
"Gepirone ER" . Adis Insight.
Archived from the original on 6 August 2016. Retrieved 13 January 2016 .
^
"FDA Rules Favorably On Efficacy Of Travivo (Gepirone ER) For Treatment Of Major Depressive Disorder" (Press release). 17 March 2016.
Archived from the original on 24 September 2017. Retrieved 23 January 2018 .
^
a
b Fabre LF, Brown CS, Smith LC, Derogatis LR (May 2011). "Gepirone-ER treatment of hypoactive sexual desire disorder (HSDD) associated with depression in women". The Journal of Sexual Medicine . 8 (5): 1411–1419.
doi :
10.1111/j.1743-6109.2011.02216.x .
PMID
21324094 .
^
a
b Fabre LF, Clayton AH, Smith LC, Goldstein I, Derogatis LR (March 2012). "The effect of gepirone-ER in the treatment of sexual dysfunction in depressed men". The Journal of Sexual Medicine . 9 (3): 821–829.
doi :
10.1111/j.1743-6109.2011.02624.x .
PMID
22240272 .
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LSD ,
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L-694247
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PNU-109291
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Pirenperone
Pizotifen
Propranolol
PRX-08066
Rauwolscine
Ritanserin
RS-127445
Sarpogrelate
SB-200646
SB-204741
SB-206553
SB-215505
SB-221284
SB-228357
SDZ SER-082
Tegaserod
Tetracyclic antidepressants (e.g.,
amoxapine ,
mianserin ,
mirtazapine )
Trazodone
Typical antipsychotics (e.g.,
chlorpromazine )
TIK-301
Yohimbine
5-HT2C
Agonists:
2Cs (e.g.,
2C-B ,
2C-E ,
2C-I ,
2C-T-2 ,
2C-T-7 ,
2C-T-21 )
5-Methoxytryptamines (
5-MeO-DET ,
5-MeO-DiPT ,
5-MeO-DMT ,
5-MeO-DPT ,
5-MT )
α-Alkyltryptamines (e.g.,
5-Cl-αMT ,
5-Fl-αMT ,
5-MeO-αET ,
5-MeO-αMT ,
α-Me-5-HT ,
αET ,
αMT )
A-372159
AL-38022A
Alstonine
CP-809101
Dimemebfe
DOx (e.g.,
DOB ,
DOC ,
DOI ,
DOM )
Ergolines (e.g.,
ALD-52 ,
cabergoline ,
dihydroergotamine ,
ergine (LSA) ,
ergotamine ,
lisuride ,
LA-SS-Az ,
LSB ,
LSD ,
LSD-Pip ,
LSH ,
LSP ,
pergolide )
Flumexadol
Lorcaserin
MDxx (e.g.,
MDA (tenamfetamine) ,
MDMA (midomafetamine) ,
MDOH ,
MMDA )
MK-212
ORG-12962
ORG-37684
Oxaflozane
PHA-57378
Phenethylamines (e.g.,
lophophine ,
mescaline )
Piperazines (e.g.,
aripiprazole ,
BZP ,
mCPP ,
quipazine ,
TFMPP )
PNU-22394
PNU-181731
Ro60-0175
Ro60-0213
Serotonin (5-HT)
Tryptamines (e.g.,
5-BT ,
5-CT ,
bufotenin ,
DET ,
DiPT ,
DMT ,
DPT ,
psilocin ,
psilocybin ,
tryptamine )
Vabicaserin
WAY-629
WAY-161503
YM-348
Antagonists:
Adatanserin
Agomelatine
Atypical antipsychotics (e.g.,
asenapine ,
clorotepine ,
clozapine ,
fluperlapine ,
iloperidone ,
melperone ,
olanzapine ,
paliperidone ,
quetiapine ,
risperidone ,
sertindole ,
ziprasidone ,
zotepine )
Captodiame
CEPC
Cinanserin
Cyproheptadine
Deramciclane
Desmetramadol
Dotarizine
Eltoprazine
Ergolines (e.g.,
amesergide ,
bromocriptine ,
LY-53857 ,
LY-215,840 ,
mesulergine ,
metergoline ,
methysergide ,
sergolexole )
Etoperidone
Fluoxetine
FR-260010
Irindalone
Ketanserin
Ketotifen
Latrepirdine (dimebolin)
Medifoxamine
Metitepine (methiothepin)
Nefazodone
Pirenperone
Pizotifen
Propranolol
Ritanserin
RS-102221
S-14671
SB-200646
SB-206553
SB-221284
SB-228357
SB-242084
SB-243213
SDZ SER-082
Tedatioxetine
Tetracyclic antidepressants (e.g.,
amoxapine ,
aptazapine ,
esmirtazapine ,
maprotiline ,
mianserin ,
mirtazapine )
TIK-301
Tramadol
Trazodone
Tricyclic antidepressants (e.g.,
amitriptyline ,
nortriptyline )
Typical antipsychotics (e.g.,
chlorpromazine ,
loxapine ,
pimozide ,
pipamperone ,
thioridazine )
Xylamidine
5-HT3 –
7
5-HT3
Agonists:
Alcohols (e.g.,
butanol ,
ethanol (alcohol) ,
trichloroethanol )
m-CPBG
Phenylbiguanide
Piperazines (e.g.,
BZP ,
mCPP ,
quipazine )
RS-56812
Serotonin (5-HT)
SR-57227
SR-57227A
Tryptamines (e.g.,
2-Me-5-HT ,
5-CT ,
bufotenidine (5-HTQ) )
Volatiles/gases (e.g.,
halothane ,
isoflurane ,
toluene ,
trichloroethane )
YM-31636
Antagonists:
Alosetron
Anpirtoline
Arazasetron
AS-8112
Atypical antipsychotics (e.g.,
clozapine ,
olanzapine ,
quetiapine )
Azasetron
Batanopride
Bemesetron (MDL-72222)
Bupropion
Cilansetron
CSP-2503
Dazopride
Dolasetron
Galanolactone
Granisetron
Hydroxybupropion
Lerisetron
Memantine
Ondansetron
Palonosetron
Ramosetron
Renzapride
Ricasetron
Tedatioxetine
Tetracyclic antidepressants (e.g.,
amoxapine ,
mianserin ,
mirtazapine )
Thujone
Tropanserin
Tropisetron
Typical antipsychotics (e.g.,
loxapine )
Volatiles/gases (e.g.,
nitrous oxide ,
sevoflurane ,
xenon )
Vortioxetine
Zacopride
Zatosetron
5-HT4
5-HT5A
5-HT6
Agonists:
Ergolines (e.g.,
dihydroergocryptine ,
dihydroergotamine ,
ergotamine ,
lisuride ,
LSD ,
mesulergine ,
metergoline ,
methysergide )
Hypidone
Serotonin (5-HT)
Tryptamines (e.g.,
2-Me-5-HT ,
5-BT ,
5-CT ,
5-MT ,
Bufotenin ,
E-6801 ,
E-6837 ,
EMD-386088 ,
EMDT ,
LY-586713 ,
N-Me-5-HT ,
ST-1936 ,
tryptamine )
WAY-181187
WAY-208466
Antagonists:
ABT-354
Atypical antipsychotics (e.g.,
aripiprazole ,
asenapine ,
clorotepine ,
clozapine ,
fluperlapine ,
iloperidone ,
olanzapine ,
tiospirone )
AVN-101
AVN-211
AVN-322
AVN-397
BGC20-760
BVT-5182
BVT-74316
Cerlapirdine
EGIS-12,233
GW-742457
Idalopirdine
Ketanserin
Landipirdine
Latrepirdine (dimebolin)
Masupirdine
Metitepine (methiothepin)
MS-245
PRX-07034
Ritanserin
Ro 04-6790
Ro 63-0563
SB-258585
SB-271046
SB-357134
SB-399885
SB-742457
Tetracyclic antidepressants (e.g.,
amoxapine ,
mianserin )
Tricyclic antidepressants (e.g.,
amitriptyline ,
clomipramine ,
doxepin ,
nortriptyline )
Typical antipsychotics (e.g.,
chlorpromazine ,
loxapine )
5-HT7
Antagonists:
Atypical antipsychotics (e.g.,
amisulpride ,
aripiprazole ,
asenapine ,
brexpiprazole ,
clorotepine ,
clozapine ,
fluperlapine ,
olanzapine ,
risperidone ,
sertindole ,
tiospirone ,
ziprasidone ,
zotepine )
Butaclamol
DR-4485
EGIS-12,233
Ergolines (e.g.,
2-Br-LSD (BOL-148) ,
amesergide ,
bromocriptine ,
cabergoline ,
dihydroergotamine ,
ergotamine ,
LY-53857 ,
LY-215,840 ,
mesulergine ,
metergoline ,
methysergide ,
sergolexole )
JNJ-18038683
Ketanserin
LY-215,840
Metitepine (methiothepin)
Ritanserin
SB-258719
SB-258741
SB-269970
SB-656104
SB-656104A
SB-691673
SLV-313
SLV-314
Spiperone
SSR-181507
Tetracyclic antidepressants (e.g.,
amoxapine ,
maprotiline ,
mianserin ,
mirtazapine )
Tricyclic antidepressants (e.g.,
amitriptyline ,
clomipramine ,
imipramine )
Typical antipsychotics (e.g.,
acetophenazine ,
chlorpromazine ,
chlorprothixene ,
fluphenazine ,
loxapine ,
pimozide )
Vortioxetine