THERAPEUTICS

Brands

• Anafranil
• see index for additional brand names

Generic?

• Yes

Class

• Tricyclic antidepressant (TCA)
• Parent drug is a potent serotonin reuptake inhibitor
• Active metabolite is a potent norepinephrine/noradrenaline reuptake inhibitor

Commonly Prescribed for

• (bold for FDA approved)
• Obsessive-compulsive disorder
• Depression
• Severe and treatment-resistant depression
• Cataplexy syndrome
• Anxiety
• Insomnia
• Neuropathic pain/chronic pain

How the Drug Works

• 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 desensitizes both serotonin 1A receptors and beta adrenergic receptors
• Since dopamine is inactivated by norepinephrine reuptake in frontal cortex, which largely lacks dopamine transporters, clomipramine can increase dopamine neurotransmission in this part of the brain

How Long Until It Works

• May have immediate effects in treating insomnia or anxiety
• Onset of therapeutic actions in depression usually not immediate, but often delayed 2 to 4 weeks
• Onset of therapeutic action in OCD can be delayed 6 to 12 weeks
• If it is not working for depression within 6 to 8 weeks, it may require a dosage increase or it may not work at all
• If it is not working for OCD within 12 weeks, 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 of depression 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
• Although the goal of treatment of OCD is also complete remission of symptoms, this may be less likely than in depression
• The goal of treatment of chronic neuropathic pain is to reduce symptoms as much as possible, especially in combination with other treatments
• 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 OCD may also need to be indefinite, starting from the time of initial treatment
• Use in other anxiety disorders and chronic pain may also need to be indefinite, but long-term treatment is not well studied in these conditions

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, especially behavioral therapy in OCD
• 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

• Lithium, buspirone, hormone (for depression and OCD)
• For the expert: consider cautious addition of fluvoxamine for treatment-resistant OCD
• Thyroid hormone (for depression)
• Atypical antipsychotics (for OCD)

Tests

• None for healthy individuals, although monitoring of plasma drug levels is potentially available at specialty laboratories for the expert
• 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