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 or 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 depressive symptoms

• Vasomotor symptoms in perimenopausal women with or without depression may improve within 1 week

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) or significantly reduced

• Once symptoms are 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

• 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 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

Desvenlafaxine: 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

• Insomnia, sedation, anxiety, dizziness

• Nausea, vomiting, constipation, decreased appetite

• Sexual dysfunction (abnormal ejaculation/orgasm, impotence)

• Sweating

• SIADH (syndrome of inappropriate antidiuretic hormone secretion)

• Hyponatremia

• 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

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 desvenlafaxine

DESVENLAFAXINE: DOSING AND USE

Usual Dosage Range

• Depression: 50 mg once daily

Dosage Forms

• Tablet (extended-release) 50 mg, 100 mg

How to Dose

• Initial dose 50 mg once daily; maximum recommended dose generally 100 mg once daily; doses up to 400 mg once daily have been shown to be effective but higher doses are associated with increased side effects

Dosing Tips

• Desvenlafaxine is the active metabolite O-desmethylvenlafaxine (ODV) of venlafaxine, and is formed as the result of CYP450 2D6

• More potent at the serotonin transporter (SERT) than at the norepinephrine transporter (NET), but has greater inhibition of NET relative to SERT compared to venlafaxine

• Nonresponders at lower doses may try higher doses to be assured of the benefits of dual SNRI action

• For vasomotor symptoms, current data suggest that a dose of 100 mg/day is effective

• Do not break or chew tablets, as this will alter controlled-release properties

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

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

• May dose up to 400 mg/day in patients who do not respond to lower doses, if tolerated