THERAPEUTICS

Brands

• Sinequan, Silenor
• see index for additional brand names

Generic?

• Yes

Class

• Tricyclic antidepressant (TCA)
• Serotonin and norepinephrine/noradrenaline reuptake inhibitor
• Antihistamine

Commonly Prescribed for

• (bold for FDA approved)
• Psychoneurotic patient with depression and/or anxiety
• Depression and/or anxiety associated with alcoholism
• Depression and/or anxiety associated with organic disease
• Psychotic depressive disorders with associated anxiety
• Involutional depression
• Manic-depressive disorder
• Insomnia (difficulty with sleep maintenance) (Silenor only)
• Pruritus/itching (topical)
• Dermatitis, atopic (topical)
• Lichen simplex chronicus (topical)
• Anxiety
• Neuropathic pain/chronic pain
• Treatment-resistant depression

How the Drug Works

• At antidepressant doses:
• Boosts neurotransmitters serotonin and norepinephrine/noradrenaline
• Blocks serotonin reuptake pump (serotonin transporter), presumably increasing serotonergic neurotransmission
• Blocks norepinephrine reuptake pump (norepinephrine transporter), presumably increasing noradrenergic neurotransmission
• Presumably by desensitizes both serotonin 1A receptors and beta adrenergic receptors
• Since dopamine is inactivated by norepinephrine reuptake in frontal cortex, which largely lacks dopamine transporters, doxepin can thus increase dopamine neurotransmission in this part of the brain
• May be effective in treating skin conditions because of its strong antihistamine properties
• At hypotic doses (3-6 mg/day):
• Selectively and potently blocks histamine 1 receptors, presumably decreasing wakefulness and thus promoting sleep

How Long Until It Works

• May have immediate effects in treating insomnia or anxiety
• Onset of therapeutic actions in depression is 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 depressive symptoms
• May also work long-term for insomnia (studied for up to 12 weeks)

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 insomnia is to improve quality of sleep, including effects on total wake time and number of nighttime awakenings.
• The goal of treatment of 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 not a cure since symptoms can recur after medicine stopped
• Treatment of 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 anxiety disorders, chronic pain, and skin conditions 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
• 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
• If Insomnia does not improve after 7-10 days, it may be a manifestation of a primary psychiatric or physical illness such as obstructive sleep apnea or restless leg syndrome, which requires independent evaluation

Best Augmenting Combos for Partial Response or Treatment Resistance

• Lithium, buspirone, thyroid hormone (for depression)
• Trazodone, GABA-ergic sedative hypnotics (for insomnia)
• Gabapentin, tiagabine, other anticonvulsants, even opiates if done by experts while monitoring carefully in difficult cases (for chronic pain)

Tests

• None for healthy individuals
• Since tricyclic and tetracyclic antidepressants are frequently associated with weight gain, before starting treatment, weigh all patients and determine if the patient is already overweight (BMI 25.0–29.9) or obese (BMI ≥30)
• Before giving a drug that can cause weight gain to an overweight or obese patient, consider determining whether the patient already has pre-diabetes (fasting plasma glucose 100–25 mg/dL), diabetes (fasting plasma glucose >126 mg/dl), or dyslipidemia (increased total cholesterol, LDL cholesterol and triglycerides; decreased HDL cholesterol), and treat or refer such patients for treatment including nutrition and weight management, physical activity counseling, smoking cessation, and medical management
• Monitor weight and BMI during treatment
• While giving a drug to a patient who has gained >5% of initial weight, consider evaluating for the presence of pre-diabetes, diabetes, or dyslipidemia, or consider switching to a different antidepressant
• EKGs may be useful for selected patients (e.g., those with personal or family history of QTc prolongation; cardiac arrhythmia; recent myocardial infarction; uncompensated heart failure; or taking agents that prolong QTc interval such as pimozide, thioridazine, selected antiarrhythmics, moxifloxacin, sparfloxacin, etc.)
• Patients at risk for electrolyte disturbances (e.g., patients on diuretic therapy) should have baseline and periodic serum potassium and magnesium measurements