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, 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 in depression

If It Works

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

• The goal of treatment of fibromyalgia and chronic neuropathic pain is to reduce symptoms as much as possible, especially in combination with other treatments

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

• Treatment of fibromyalgia and chronic neuropathic pain may reduce symptoms, but rarely eliminates them completely, and is not a cure since symptoms can recur after medicine is stopped

• Continue treatment of depression until all symptoms are gone (remission)

• Once symptoms of depression 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

• Use in fibromyalgia and chronic neuropathic pain may also need to be indefinite, but long-term treatment is not well studied in these conditions

If It Doesn’t Work

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

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

• Some depressed 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

• Augmentation experience is limited compared to other antidepressants

• Benzodiazepines can reduce insomnia and anxiety

• Adding other agents to milnacipran for treating depression could follow the same practice for augmenting SSRIs or other SNRIs if done by experts while monitoring carefully in difficult cases

• Although no controlled studies and little clinical experience, adding other agents for treating fibromyalgia and chronic neuropathic pain could theoretically include gabapentin, tiagabine, other anticonvulsants, or even opiates if done by experts while monitoring carefully in difficult cases

• Mirtazapine, bupropion, reboxetine, atomoxetine (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

• Hypnotics or trazodone for insomnia

• Classically, lithium, buspirone, or thyroid hormone

Tests

• Check blood pressure before initiating treatment and regularly during treatment