Nortriptyline (Pamelor) is the major active metabolite of amitriptyline. Sometimes nortriptyline is referred to as a second generation TCA (amitriptyline being the first generation). Nortriptyline is a norepinephrine reuptake inhibitor (NRI) with no significant serotonergic activity. It is similar to bupropion (Wellbutrin), although with more side effects and greater toxicity in overdose. Because it is not serotonergic, nortriptyline could be safely combined with an MAOI for refractory depression (Thomas & Shin et al, 2015).
Nortriptyline is arguably underutilized because it is superior to other TCAs in terms of safety and tolerability (Gillman, 2007). It has a relatively wide margin between therapeutic effects and side effects/toxicity. Nortriptyline causes the least orthostatic hypotension among the TCAs, so the individual is less likely to become lightheaded and fall—Pamelor “keeps Pam’s head pointed North”. It can be effective for SSRI non-responders. It is one of two antidepressants (citalopram) with demonstrated benefit for post-stroke depression.
Not all TCAs combine well with SSRIs, but nortriptyline plus sertraline (Zoloft) or escitalopram (Lexapro) is considered a favorable pairing. Nortriptyline has been shown more effective than escitalopram for depression in individuals with high C-reactive protein, which is a general marker of inflammation (Uher et al, 2014).
Sedation from nortriptyline is by antihistamine effect. The label instructs to give nortriptyline at bedtime. Considering its stimulating properties, AM dosing may be more appropriate for some patients.
Nortriptyline has been used off-label for smoking cessation and ADHD, which is reasonable because its mechanism of action resembles that of atomoxetine (approved for ADHD) and bupropion (approved for smoking, used off-label for ADHD).
Think twice before prescribing nortriptyline to anyone at risk of overdosing on pills. Risk of mortality in single-drug overdose is only slightly less than with amitriptyline.
Initial milligram dose for nortriptyline is the same as amitriptyline and imipramine, although the FDA max for nortriptyline (150 mg) is lower than for amitriptyline/imipramine (300 mg).
Dosing: According to the label, the target dose for depression is 50–150 mg HS; Start: 25–50 mg HS and increase by 25–50 mg/day q 2–3 days; Max dose is 150 mg/day; May give in divided doses, or in AM; Use lower dose for elderly patients. Taper dose gradually to stop. Therapeutic serum range is about 50–150 ng/mL, which is easy to remember since the recommended dose range is 50–150 mg. Serum level does not necessarily correlate with clinical efficacy.
See Tricyclic antidepressants (TCAs)
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