1. BIOLOGICAL THERAPIES
MARIA FE SALVADOR NAVARRETE,MD

2. Anticonvulsants: Gabapentin, Pregabalin,
Tiagabine, Levetiracetam, Topiramate, and
Zonisamide
 Gabapentin
 Gabapentin indirectly increases brain γ-aminobutyric acid
(GABA) levels.
 It is well absorbed, but its bioavailability decreases as doses are
increased, because of saturation of the neutral amino acid
membrane transporter system in the gut.
 Because higher amounts are not absorbed, doses should not
exceed 1,800 mg per single dose or 5,400 mg a day.
 Gabapentin absorption is unaffected by food.
 Steady-state half-life of 5 to 9 hours is reached in 2 days when
taken three times a day.
 Gabapentin does not bind to plasma proteins and is not
metabolized.
 It is excreted unchanged in the urine.

3.  Therapeutic Indication
 hypnotic agent, because of its sedating effects.
 anxiolytic properties,
 panic attacks and social anxiety disorde
 Gabapentin decreases craving for alcohol, helping patients
to remain abstinent, and facilitates detoxification.
 gabapentin following benzodiazepine-facilitated alcohol
detoxification.
 Because gabapentin is renally excreted, it is well suited for
use among patients with liver disease.
 To the extent that gabapentin reduces alcohol use among
patients with bipolar disorder, it may prove useful as an
adjunct to standard mood stabilizer regimens.

4.  Gabapentin is approved by the US Food and
Drug Administration (FDA) for the treatment of
postherpetic neuralgia.
 trigeminal neuralgia; central pain syndromes;
and compression neuropathies, such as carpal
tunnel syndrome, radiculopathies, and meralgia
paresthetica.
 Pregabalin, an analog of gabapentin, has been
approved for the management of neuropathic
pain associated with diabetic peripheral
neuropathy and postherpetic neuralgia.

5.  Pregabalin has been found to be of benefit to some
patients with generalized anxiety disorder. In
studies, no consistent dose response relationship
was found, although 300-mg pregabalin per day was
more effective than 150 mg or 450 mg.
 Although rejected for that indication by the FDA, the
Committee for Medicinal Products for Human Use
(CHMP) of the European MedicinesAgency issued a
positive opinion recommending marketing
authorization of pregabalin. Some patients with
panic disorder or social anxiety disorder may benefit
from pregabalin, but little evidence supports its
routine use in treating those disorders.

6.  Clinical Guidelines
 Pregabalin exhibits linear pharmacokinetics. It is
extremely and rapidly absorbed in proportion to
its dose.The time to maximal plasma
concentration is about 1 hour and to steady state
within 24 to 48 hours. Pregabalin demonstrates
high bioavailability, and has a mean elimination
half-life of about 6.5 hours. Food does not affect
absorption. Pregabalin does not bind to plasma
proteins and is excreted virtually unchanged (less
than 2 percent metabolism) by the kidneys

7.  The most common adverse events associated
with pregabalin use are dizziness,
somnolence, blurred vision, peripheral
edema, amnesia or loss of memory, and
tremors. Pregabalin potentiates sedating
effects of alcohol, antihistamines,
benzodiazepines, and other central nervous
system (CNS) depressants. It remains to be
seen if pregabalin is associated with
benzodiazepine-type withdrawal symptoms.

8. TOPIRAMATE
 Topiramate
 Topiramate is a selective inhibitor of Glu AMPA receptors,
blocks Na+ receptors, and has indirect GABAergic activity.
 It potentiates the action of GABA at a
non–benzodiazepine-, non–barbiturate-sensitive
GABAA receptor, is rapidly and completely absorbed, and
has a steady-state half-life of 21 hours.
 Food does not affect its absorption.
 It is 15 percent protein bound in the plasma and 70 percent
of an oral dose of topiramate is excreted unchanged in the
urine, together with small amounts of several inactive
metabolites.
 Topiramate is an inhibitor of state-dependent sodium
channels.

9.  Therapeutic Indications
 Despite initial reports of mood-stabilizing properties, a series of
large, placebo-controlled studies failed to find any evidence of
antimanic activity.
 The fact that some patients lose a substantial amount of weight
while taking topiramate is exploited in psychiatry, mainly to
counteract the weight gain caused by many psychotropic drugs.
 Topiramate has been shown to benefit patients with primary
alcoholism and posttraumatic stress disorder.
 Topiramate may reduce the frequency of cutting and other forms
of self-mutilating behavior in patients with borderline personality
disorder.
 It is effective in treating neuropathic pain and migraine and is
also highly effective in treating binge-eating disorder.

10. SIDE EFFECTS
 psychomotor slowing; speech and language
problems, especially word-finding difficulties;
somnolence; dizziness; ataxia; nystagmus; and
paresthesias
 dose-related adverse effects are fatigue,
nervousness, poor concentration, confusion,
taste perversion, depression, anorexia, anxiety,
mood problems, weight loss, and tremor.
 Some 1.5 percent of persons taking topiramate
develop renal calculi, a rate ten times that
associated with placebo. Patients at risk for
calculi should be encouraged to drink

11. TIAGABINE
 Tiagabine
 Tiagabine is a potent and selective reuptake inhibitor of
GABA.
 It also has mild blocking effects of H1, serotonin IB,
benzodiazepine, and chloride channel receptors. More than
95 percent of tiagabine is rapidly absorbed.
 The rate of absorption is slowed by food. Absolute
bioavailability of tiagabine is 95 percent, and it is 96
percent protein bound.
 It has a half-life of 7 to 9 hours and is metabolized by the
hepatic CYP450 3A system.Tiagabine concentrations are
about 40 percent lower in the evening than in the morning.

12.  Tiagabine is occasionally used as an anxiolytic
or hypnotic agent in patients who have not
responded to, or tolerated, standard
treatments

13.  Animal studies have found teratogenic effects in rats.
Ophthalmic changes can occur with chronic use
 . CNS side effects include sedation, cognitive impairment, ataxia,
dizziness, tremor, paresthesias, confusion, and depression.
 Other side effects include ecchymosis, nausea, abdominal pain,
muscle weakness, and flushing.Cases of serious rash can occur,
including Stevens-Johnson syndrome. Lower doses of tiagabine
should be used in patients with hepatic impairment.
 Patients being treated with tiagabine for bipolar disorder have
experienced new-onset seizures. Reports of seizures in patients
without epilepsy being treated with tiagabine have prompted an
FDA warning about its use. Consequently, this drug should not be
considered for off-label psychiatric use.

14. ZONISAMIDE
 Zonisamide
 Zonisamide is sometimes used as an alternative treatment
for acute mania and as a weight loss agent for drug-induced
weight gain.
 Zonisamide blocks sodium channels and may weakly
potentiate dopamine and serotonin activity. It also inhibits
carbonic anhydrase. Some evidence suggests that it might
block calcium channels. Zonisamide is metabolized by the
hepatic CYP450 3A system, so enzyme-inducing agents,
such as carbamazepine, alcohol, and phenobarbital,
increase the clearance and reduce P.1011

the availability of the drug. Zonisamide does not affect the
metabolism of other drugs.

15.  Zonisamide is a sulfonamide and, thus, may cause
fatal rash and blood dyscrasias, although these
events are rare.
 About 4 percent of patients develop kidney stones.
The most common side effects are drowsiness,
cognitive impairment, insomnia, ataxia, nystagmus,
paresthesia, speech abnormalities, constipation,
diarrhea, nausea, and dry mouth.
 Weight loss is also a common side effect, which has
been exploited as a therapy for patients who have
gained weight during treatment with psychotropics
or who have ongoing difficulty controlling their
eating.

16. LEVETIRACETAM
 Levetiracetam has been used to treat acute
mania, as add-on therapy to antidepressants
to prevent the emergence of mania or
cycling, and as an anxiolytic.
 The CNS effects of levetiracetam are poorly
understood, but it appears to indirectly
enhance GABA inhibition.

17.  The most common side effects of
levetiracetam are drowsiness, dizziness,
ataxia, diplopia, memory impairment,
apathy, and paresthesia. More notably, some
patients develop behavioral disturbances
during treatment, and hallucinations can
occur. Suicidality was noted in a few patients
during clinical trials.

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19.  Antihistamines
 In clinical psychiatry, certain antihistamines (antagonists of
histamine H1 receptors) are used to treat neuroleptic-
induced parkinsonism and neuroleptic-induced acute
dystonia and also as hypnotics and anxiolytics.
 Diphenhydramine (Benadryl) is used to treat neuroleptic-
induced parkinsonism and neuroleptic-induced acute
dystonia and sometimes as a hypnotic.
 Hydroxyzine hydrochloride (Atarax) and hydroxyzine
pamoate (Vistaril) are used as anxiolytics. Promethazine
(Phenergan) is used for its sedative and anxiolytic effects.

20.  Cyproheptadine (Periactin) has been used for the
treatment of anorexia nervosa and inhibited male
and female orgasm caused by serotonergic agents.
 The antihistamines most commonly used in
psychiatry are listed inTable 36.7-1. Fexofenadine
(Allegra), loratadine (Claritin), and cetirizine (Zyrtec)
are less commonly used in psychiatric practice.
 Terfenadine (Seldane) and astemizole (Hismanal)
were withdrawn from commercial availability
because they were associated with serious cardiac
arrhythmias when coadministered with some drugs
(e.g., nefazodone [Serzone], selective serotonin
reuptake inhibitors [SSRIs]).

21.  Therapeutic Indications
 Antihistamines are useful as a treatment for
neuroleptic-induced parkinsonism, neuroleptic-
induced acute dystonia, and neuroleptic-induced
akathisia
 They are an alternative to anticholinergics and
amantadine for these purposes.
 The antihistamines are relatively safe hypnotics,
but they are not superior to the
benzodiazepines, which have been much better
studied in terms of efficacy and safety.

22.  The antihistamines have not been proved
effective for long-term anxiolytic therapy;
therefore, either the benzodiazepines,
buspirone (BuSpar), or SSRIs are preferable
for such treatment.
 Cyproheptadine is sometimes used to treat
impaired orgasms, especially delayed orgasm
resulting from treatment with serotonergic
drugs.

23.  Because it promotes weight gain,
cyproheptadine may be of some use in the
treatment of eating disorders, such as anorexia
nervosa.
 Cyproheptadine can reduce recurrent
nightmares with posttraumatic themes.
 The antiserotonergic activity of cyproheptadine
may counteract the serotonin syndrome caused
by concomitant use of multiple serotonin-
activating drugs, such as SSRIs and monoamine
oxidase inhibitors (MAOIs).

24. Precautions and Adverse
Reactions
 sedation, dizziness, and hypotension, all of which can be severe in
elderly persons, who are also likely to be affected by the anticholinergic
effects of those drugs.
 Paradoxical excitement and agitation are adverse effects seen in a small
number of persons.
 Poor motor coordination can result in accidents; therefore, persons
should be warned about driving and operating dangerous machinery.
 Other common adverse effects include epigastric distress, nausea,
vomiting, diarrhea, and constipation.
 Because of mild anticholinergic activity, some people experience dry
mouth, urinary retention, blurred vision, and constipation. For this
reason also, antihistamines should be used only at very low doses, if at
all, by persons with narrow-angle glaucoma or obstructive GI, prostate,
or bladder conditions.
 A central anticholinergic syndrome with psychosis may be induced by
either cyproheptadine or diphenhydramine.

25. DRUG INTERACTIONS
 The sedative property of antihistamines can be
additive with other central nervous system (CNS)
depressants, such as alcohol, other sedative-
hypnotic drugs, and many psychotropic drugs,
including tricyclic drugs and dopamine receptor
antagonists (DRAs).
 The anticholinergic activity can also be additive
with that of other anticholinergic drugs and can
sometimes result in severe anticholinergic
symptoms or intoxication.The beneficial effects
of SSRIs can be antagonized by cyproheptadine.

26.  H1 antagonists may eliminate the wheal and
induration that form the basis of allergy skin
tests. Promethazine can interfere with
pregnancy tests and can increase blood
glucose concentrations. Diphenhydramine
may yield a false-positive urine test result for
phencyclidine (PCP). Hydroxyzine use can
falsely elevate the results of certain tests for
urinary 17-hydroxycorticosteroids.

27.  Intravenous (IV) administration of 25 to 50 mg of
diphenhydramine is an effective treatment for
neuroleptic-induced acute dystonia, which may
immediately disappear.Treatment with 25 mg
three times a day—up to 50 mg four times a
day, if necessary—can be used to treat
neuroleptic-induced parkinsonism, akinesia, and
buccal movements. Diphenhydramine can be
used as a hypnotic at a 50-mg dose for mild
transient insomnia. Doses of 100 mg have not
been shown to be superior to doses of 50 mg, but
they produce more anticholinergic effects than
doses of 50 mg.

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