How Long Until It Works

• Onset of therapeutic actions usually not immediate, but often delayed 2–4 weeks

• If it is not working within 6–8 weeks for depression, it may require a dosage increase or it may not work at all

• May continue to work for many years to prevent relapse of symptoms

If It Works

• The goal of treatment is complete remission of current symptoms as well as prevention of future relapses

• Treatment most often reduces or even eliminates symptoms, but not a cure since symptoms can recur after medicine stopped

• Continue treatment until all symptoms are gone (remission)

• Once symptoms gone, continue treating for 1 year for the first episode of depression

• For second and subsequent episodes of depression, treatment may need to be indefinite

If It Doesn’t Work

• Many patients have only a partial response where some symptoms are improved but others persist (especially insomnia, fatigue, and problems concentrating)

• Other patients may be nonresponders, sometimes called treatment-resistant or treatment-refractory

• Consider increasing dose, switching to another agent or adding an appropriate augmenting agent

• Consider psychotherapy

• Consider evaluation for another diagnosis or for a comorbid condition (e.g., medical illness, substance abuse, etc.)

• Some patients may experience apparent lack of consistent efficacy due to activation of latent or underlying bipolar disorder, and require antidepressant discontinuation and a switch to a mood stabilizer

Best Augmenting Combos for Partial Response or Treatment Resistance

• Trazodone, especially for insomnia

• SSRIs, SNRIs, mirtazapine (use combinations of antidepressants with caution as this may activate bipolar disorder and suicidal ideation)

• Modafinil, especially for fatigue, sleepiness, and lack of concentration

• Mood stabilizers or atypical antipsychotics for bipolar depression, psychotic depression or treatment-resistant depression

• Benzodiazepines for anxiety

• Hypnotics for insomnia

• Classically, lithium, buspirone, or thyroid hormone

Tests

• None for healthy individuals

REBOXETINE: SIDE EFFECTS

How Drug Causes Side Effects

• Norepinephrine increases in parts of the brain and body and at receptors other than those that cause therapeutic actions (e.g., unwanted actions of norepinephrine on acetylcholine release causing constipation and dry mouth, etc.)

• Most side effects are immediate but often go away with time

Notable Side Effects

• Insomnia, dizziness, anxiety, agitation

• Dry mouth, constipation

• Urinary hesitancy, urinary retention

• Sexual dysfunction (impotence)

• Dose-dependent hypotension

Life-Threatening or Dangerous Side Effects

• Rare seizures

• Rare induction of mania

• Rare activation of suicidal ideation and behavior (suicidality) (short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo beyond age 24)

Weight Gain

• Reported but not expected

Sedation

• Reported but not expected

What to Do About Side Effects

• Wait

• Wait

• Wait

• Lower the dose

• In a few weeks, switch or add other drugs

Best Augmenting Agents for Side Effects

• For urinary hesitancy, give an alpha 1 blocker such as tamsulosin

• Often best to try another antidepressant monotherapy prior to resorting to augmentation strategies to treat side effects

• Trazodone or a hypnotic for drug-induced insomnia

• Benzodiazepines for drug-induced anxiety and activation

• Mirtazapine for drug-induced insomnia or anxiety

• Many side effects are dose-dependent (i.e., they increase as dose increases, or they reemerge until tolerance redevelops)

• Many side effects are time-dependent (i.e., they start immediately upon dosing and upon each dose increase, but go away with time)

• Activation and agitation may represent the induction of a bipolar state, especially a mixed dysphoric bipolar II condition sometimes associated with suicidal ideation, and require the addition of lithium, a mood stabilizer or an atypical antipsychotic, and/or discontinuation of reboxetine

REBOXETINE: DOSING AND USE

Usual Dosage Range

• 8 mg/day in 2 doses (10 mg usual maximum daily dose)

Dosage Forms

• Tablet 2 mg, 4 mg scored

How to Dose

• Initial 2 mg/day twice a day for 1 week, 4 mg/day twice a day for second week

Dosing Tips

• When switching from another antidepressant or adding to another antidepressant, dosing may need to be lower and titration slower to prevent activating side effects (e.g., 2 mg in the daytime for 2–3 days, then 2 mg bid for 1–2 weeks)

• Give second daily dose in late afternoon rather than at bedtime to avoid undesired activation or insomnia in the evening

• May not need full dose of 8 mg/day when given in conjunction with another antidepressant

• Some patients may need 10 mg/day or more if well tolerated without orthostatic hypotension and if additional efficacy is seen at high doses in difficult cases

• Early dosing in patients with panic and anxiety may need to be lower and titration slower, perhaps with the use of concomitant short-term benzodiazepines to increase tolerability

Overdose

• Postural hypotension, anxiety, hypertension

Long-Term Use

• Safe

Habit Forming

• No

How to Stop

• Taper not necessary

Pharmacokinetics

• Metabolized by CYP450 3A4

• Inhibits CYP450 2D6 and 3A4 at high doses

• Elimination half-life approximately 13 hours

Drug Interactions

• Tramadol increases the risk of seizures in patients taking an antidepressant

• May need to reduce reboxetine dose or avoid concomitant use with inhibitors of CYP450 3A4, such as azole and antifungals, macrolide antibiotics, fluvoxamine, nefazodone, fluoxetine, sertraline, etc.

• Via CYP450 2D6 inhibition, reboxetine could theoretically interfere with the analgesic actions of codeine, and increase the plasma levels of some beta blockers and of atomoxetine and TCAs

• Via CYP450 2D6 inhibition, reboxetine could theoretically increase concentrations of thioridazine and cause dangerous cardiac arrhythmias

• Via CYP450 3A4 inhibition, reboxetine may increase the levels of alprazolam, buspirone, and triazolam

• Via CYP450 3A4 inhibition, reboxetine could theoretically increase concentrations of certain cholesterol lowering HMG CoA reductase inhibitors, especially simvastatin, atorvastatin, and lovastatin, but not pravastatin or fluvastatin, which would increase the risk of rhabdomyolysis; thus, coadministration of reboxetine with certain HMG CoA reductase inhibitors should proceed with caution

• Via CYP450 3A4 inhibition, reboxetine could theoretically increase the concentrations of pimozide, and cause QTc prolongation and dangerous cardiac arrhythmias

• Use with ergotamine may increase blood pressure

• Hypokalemia may occur if reboxetine is used with diuretics

• Use with caution with MAO inhibitors, including 14 days after MAOIs are stopped