Pregnancy

• Risk Category not formally assessed by the US FDA

• Not recommended for use during pregnancy

Breast Feeding

• Some drug is found in mother’s breast milk

✽ Not recommended for use during pregnancy

• Immediate postpartum period is a high-risk time for depression, especially in women who have had prior depressive episodes, so drug may need to be reinstituted late in the third trimester or shortly after childbirth to prevent a recurrence during the postpartum period

• Must weigh benefits of breast feeding with risks and benefits of antidepressant treatment versus nontreatment to both the infant and the mother

• For many patients, this may mean continuing treatment during breast feeding

TIANEPTINE: THE ART OF PSYCHOPHARMACOLOGY

Potential Advantages

• Elderly patients

Potential Disadvantages

• Patients who have difficulty being compliant with multiple daily dosing

Primary Target Symptoms

• Depressed mood

• Symptoms of anxiety

Pearls

✽ Possibly a unique mechanism of action

• However, mechanism of action not well understood

• Not marketed widely throughout the world, but mostly in France

Suggested Reading

Brink CB, Harvey BH, Brand L. Tianeptine: a novel atypical antidepressant that may provide new insights into the biomolecular basis of depression. Recent Patents CNS Drug Discov 2006;1(1):29–41.

Kasper S, McEwen BS. Neurobiological and clinical effects of the antidepressant tianeptine. CNS Drugs 2008;22(1):15–26.

Svenningsson P, Bateup H, Qi H, et al. Involvement of AMPA receptor phosphorylation in antidepressant actions with special reference to tianeptine. Eur J Neuorsci 2007;26:3509–17.

Wagstaff AJ, Ormrod D, Spencer CM. Tianeptine: a review of its use in depressive disorders. CNS Drugs 2001;15(3):231–59.

Wilde MI, Benfield P. Tianeptine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depression and coexisting anxiety and depression. Drugs 1995;49(3):411–39.

TOPIRAMATE

TOPIRAMATE: THERAPEUTICS

Brands

• Topamax

• Epitomax

• Topamac

• Topimax

• Trokendi XR

• Qsymia

see index for additional brand names

Generic?

Yes (not for Qsymia)

Class

• Anticonvulsant, voltage-sensitive sodium channel modulator

Commonly Prescribed for

(bold for FDA approved)

• Partial onset seizures (for immediate release: adjunctive for adults and pediatric patients 2–16 years of age; for extended release: monotherapy for patients 10 years and older, adjunctive for patients 6 years and older)

• Primary generalized tonic-clonic seizures (adjunctive; adults and pediatric patients 2–16 years of age)

• Seizures associated with Lennox-Gastaut Syndrome (2 years of age or older for immediate release, 6 years of age and older for extended release (adjunct))

• Migraine prophylaxis

• Chronic weight management (adjunct to reduced calorie diet and increased physical activity) in adults with an initial body mass index (BMI) of at least 30 kg/m² (obese) or at least 27 kg/m² (overweight) in the presence of at least one weight-related comorbid condition [in combination with phentermine (Qsymia)]

• Bipolar disorder (adjunctive; no longer in development)

• Psychotropic drug-induced weight gain

• Binge-eating disorder

How the Drug Works

✽ Blocks voltage-sensitive sodium channels by an unknown mechanism

• Inhibits release of glutamate

• Potentiates activity of gamma-aminobutyric acid (GABA)

• Carbonic anhydrase inhibitor

How Long Until It Works

• Should reduce seizures by 2 weeks

• Not clear that it has mood-stabilizing properties, but some bipolar patients may respond and if so, it may take several weeks to months to optimize an effect on mood stabilization

If It Works

• The goal of treatment is complete remission of symptoms (e.g., mania, seizures, migraine)

• Continue treatment until all symptoms are gone or until improvement is stable and then continue treating indefinitely as long as improvement persists

• Continue treatment indefinitely to avoid recurrence of mania, seizures, and headaches

If It Doesn’t Work (for bipolar disorder)

✽ May be effective only in a subset of bipolar patients, in some patients who fail to respond to other mood stabilizers, or it may not work at all

✽ Consider increasing dose or switching to another agent with better demonstrated efficacy in bipolar disorder

Best Augmenting Combos for Partial Response or Treatment Resistance

• Topiramate is itself a second-line augmenting agent for numerous other anticonvulsants, lithium, and antipsychotics in treating bipolar disorder

Tests

✽ Baseline and periodic serum bicarbonate levels to monitor for hyperchloremic, non-anion gap metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis)

TOPIRAMATE: SIDE EFFECTS

How Drug Causes Side Effects

• CNS side effects theoretically due to excessive actions at voltage-sensitive sodium channels

• Weak inhibition of carbonic anhydrase may lead to kidney stones and paresthesias

• Inhibition of carbonic anhydrase may also lead to metabolic acidosis

Notable Side Effects

✽ Sedation, asthenia, dizziness, ataxia, parasthesia, nervousness, nystagmus, tremor

✽ Nausea, appetite loss, weight loss

• Blurred or double vision, mood problems, problems concentrating, confusion, memory problems, psychomotor retardation, language problems, speech problems, fatigue, taste perversion

Life-Threatening or Dangerous Side Effects

✽ Metabolic acidosis

✽ Kidney stones

• Secondary angle-closure glaucoma

• Oligohidrosis and hyperthermia (more common in children)

• Sudden unexplained deaths have occurred in epilepsy (unknown if related to topiramate use)

• Rare activation of suicidal ideation and behavior(suicidality)

Weight Gain

• Reported but not expected

✽ Patients may experience weight loss

Sedation

• Many experience and/or can be significant in amount

What to Do About Side Effects

• Wait

• Wait

• Wait

• Take at night to reduce daytime sedation

• Increase fluid intake to reduce the risk of kidney stones

• Switch to another agent

Best Augmenting Agents for Side Effects

• Many side effects cannot be improved with an augmenting agent

TOPIRAMATE: DOSING AND USE

Usual Dosage Range

• Adults, immediate release: 200–400 mg/day in 2 divided doses for epilepsy; 50–300 mg/day for adjunctive treatment of bipolar disorder

• Adults, extended release: 200–400 mg/day as adjunct for partial onset seizures seizures; 400 mg/day as adjunct for primary generalized tonic clonic seizures; 400 mg/day as monotherapy for seizures

Dosage Forms

• Tablet 25 mg, 100 mg, 200 mg

• Sprinkle capsule 15 mg, 25 mg

• Extended release capsule 25 mg, 50 mg, 100 mg, 200 mg

How to Dose

• Adults (immediate release): initial 25–50 mg/day; increase each week by 50 mg/day; administer in 2 divided doses; maximum dose generally 1,600 mg/day

• Adults (extended release, adjunct for seizures): initial 25–50 mg once daily; increase weekly by 25–50 mg

• Seizures (extended release, monotherapy, patients ages 10 and older): initial 50 mg once daily; increase by 50 mg weekly for 4 weeks, increase by 100 mg weekly for weeks 5 and 6; recommended dose 400 mg/day

• Seizures (immediate release, ages 2–16): see Children and Adolescents