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

• By contrast, for generalized anxiety, onset of response and increases in remission rates may still occur after 8 weeks, and for up to 6 months after initiating dosing

• 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), especially in depression and whenever possible in anxiety disorders

• 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

• Use in anxiety disorders may also 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

• Some patients who have an initial response may relapse even though they continue treatment, sometimes called “poop-out”

• 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

✽ Mirtazapine (“California rocket fuel”; a potentially powerful dual serotonin and norepinephrine combination, but observe for activation of bipolar disorder and suicidal ideation)

• Bupropion, reboxetine, nortriptyline, desipramine, maprotiline, atomoxetine (all potentially powerful enhancers of noradrenergic action, but observe for activation of 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

• If all else fails for anxiety disorders, consider gabapentin or tiagabine

• Hypnotics or trazodone for insomnia

• Classically, lithium, buspirone, or thyroid hormone

Tests

• Check blood pressure before initiating treatment and regularly during treatment

Venlafaxine: side effects How Drug Causes Side Effects

• Theoretically due to increases in serotonin and norepinephrine concentrations at receptors in parts of the brain and body other than those that cause therapeutic actions (e.g., unwanted actions of serotonin in sleep centers causing insomnia, 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

• Most side effects increase with higher doses, at least transiently

• Headache, nervousness, insomnia, sedation

• Nausea, diarrhea, decreased appetite

• Sexual dysfunction (abnormal ejaculation/orgasm, impotence)

• Asthenia, sweating

• SIADH (syndrome of inappropriate antidiuretic hormone secretion)

• Hyponatremia

• Dose-dependent increase in blood pressure

Life-Threatening or Dangerous Side Effects

• Rare seizures

• Rare induction of hypomania

• 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

• Possible weight loss, especially short-term

Sedation

• Occurs in significant minority

• May also be activating in some patients

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

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

• Trazodone or a hypnotic for insomnia

• Bupropion, sildenafil, vardenafil, or tadalafil for sexual dysfunction

• Benzodiazepines for jitteriness and anxiety, especially at initiation of treatment and especially for anxious patients

• Mirtazapine for insomnia, agitation, and gastrointestinal side effects

• 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 venlafaxine

VENLAFAXINE: DOSING AND USE

Usual Dosage Range

• Depression: 75–225 mg/day, once daily (extended-release) or divided into 2–3 doses (immediate-release)

• GAD: 150–225 mg/day

Dosage Forms

• Capsule (extended-release) 37.5 mg, 75 mg, 150 mg

• Tablet (extended-release) 37.5 mg, 75 mg, 150 mg, 225 mg

• Tablet 25 mg scored, 37.5 mg scored, 50 mg scored, 75 mg scored, 100 mg scored

How to Dose

• Initial dose 37.5 mg once daily (extended-release) or 25–50 mg divided into 2–3 doses (immediate-release) for a week, if tolerated; increase daily dose generally no faster than 75 mg every 4 days until desired efficacy is reached; maximum dose generally 375 mg/day

• Usually try doses at 75 mg increments for a few weeks prior to incrementing by an additional 75 mg

Dosing Tips

• At all doses, potent serotonin reuptake blockade

• 75–225 mg/day may be predominantly serotonergic in some patients, and dual serotonin and norepinephrine acting in other patients

• 225–375 mg/day is dual serotonin and norepinephrine acting in most patients

✽ Thus, nonresponders at lower doses should try higher doses to be assured of the benefits of dual SNRI action

• At very high doses (e.g., >375 mg/day), dopamine reuptake blocked as well in some patients

• Up to 600 mg/day has been given for heroic cases

• Venlafaxine has an active metabolite O-desmethylvenlafaxine (ODV), which is formed as the result of CYP450 2D6

• Thus, CYP450 2D6 inhibition reduces the formation of ODV, but this is of uncertain clinical significance

✽ Consider checking plasma levels of ODV and venlafaxine in nonresponders who tolerate high doses, and if plasma levels are low, experts can prudently prescribe doses above 375 mg/day while monitoring closely

• Do not break or chew venlafaxine XR capsules, as this will alter controlled release properties

✽ For patients with severe problems discontinuing venlafaxine, dosing may need to be tapered over many months (i.e., reduce dose by 1% every 3 days by crushing tablet and suspending or dissolving in 100 mL of fruit juice, and then disposing of 1 mL while drinking the rest; 3–7 days later, dispose of 2 mL, and so on). This is both a form of very slow biological tapering and a form of behavioral desensitization (not for XR)

• For some patients with severe problems discontinuing venlafaxine, it may be useful to add an SSRI with a long half-life, especially fluoxetine, prior to taper of venlafaxine; while maintaining fluoxetine dosing, first slowly taper venlafaxine and then taper fluoxetine

• Be sure to differentiate between reemergence of symptoms requiring reinstitution of treatment and withdrawal symptoms

Overdose

• Can be lethal; may cause no symptoms; possible symptoms include sedation, convulsions, rapid heartbeat

• Fatal toxicity index data from the U.K. suggest a higher rate of deaths from overdose with venlafaxine than with SSRIs

• Unknown whether this is related to differences in patients who receive venlafaxine or to potential cardiovascular toxicity of venlafaxine

Long-Term Use

• See doctor regularly to monitor blood pressure, especially at doses >225 mg/day

Habit Forming

• No

How to Stop

• Taper to avoid withdrawal effects (dizziness, nausea, stomach cramps, sweating, tingling, dysesthesias)

• Many patients tolerate 50% dose reduction for 3 days, then another 50% reduction for 3 days, then discontinuation

• If withdrawal symptoms emerge during discontinuation, raise dose to stop symptoms and then restart withdrawal much more slowly

✽ Withdrawal effects can be more common or more severe with venlafaxine than with some other antidepressants