BIOLOGICAL THERAPIESMARIA FE SALVADOR NAVARRETE,MD

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.

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.

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.

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 Medicines Agency 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.

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

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.

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.

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.

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

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.

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

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.

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.

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.

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.

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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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.

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 in Table 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]).

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.

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.

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).

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.

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.

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.

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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