Nortriptyline for Depression

Nortriptyline (Pamelor, Aventyl) is a older and inexpensive tricyclic which is as effective or better than the SSRIs.  It is a dual action agent, increasing both norepinepherine and serotonin effects.  While it is quite popular among major university researchers, it is not used as often by clinical psychiatrists, since it is not being heavily promoted by any drug company due to its low cost.  

Nortriptyline is an excellent initial anti-depressant or for treatment-resistant depression.  It causes no weight gain.  It’s most common side-effect is dry mouth, which is easily relieved by bethanechol.  Other side effects include dizziness, constipation, and increased heart rate.  These may improve with time, but 15-20% of patients will have to stop nortriptyline due to side-effects, a typical rate for other anti-depressants.  Patients often need to try more than one antidepressant to find a good match.  Stool softeners and yogurt may help the constipation.  Nortriptyline has a high safety index in overdose cases according to a very large British study.  

Because of a somewhat increased heart rate and other mild cardiac effects, some authors, especially those funded by competing brandname manufacturers, state that nortriptyline may not be a good choice for the elderly, although it has been shown effective and safe for the elderly in several recent studies by major American universities.  Extensive epidemiologic research covering roughly 100,000 heart attack victims have clearly demonstrated that anti-depressants probably have a small favorable effect in preventing heart attacks and that, in any case, there is no advantage in this regard to the SSRIs and newer anti-depressants compared with the older tricyclics, especially in the case of nortriptyline, which has an excellent Safety Index in overdose cases (see Tricyclic Mortality).   

Nortriptyline may not the best choice for someone with diabetes.  Tricyclics in general have not been found very successful with child and teenage depression, although neither have any other anti-depressants with the possible exception of fluoxetine, the only medication currently recommended for minors in the United Kingdom.  Avoidant personalities may not do as well on nortriptyline and borderlines may do better on fluoxetine (Compr Psychiatry 2003 Jan-Feb;44(1):35-43.), while other personalities disorders or those without personality disorders may do better on nortriptyline.  Young adults, especially women, may do a little better on an SSRI like citalopram (Celexa), while other adults, and especially those with melancholia, do better on nortriptyline.  Of course, each person is unique, so what works for the average might not work for you.  

Checking the nortriptyline blood one time after at least one week of treatment is sometimes helpful in choosing the best dose, especially in those not responding quickly or who are responding but are suffering significant side-effects.  Taking the medicine as a single dose at bedtime is convenient, helps with sleep, and minimizes side-effects.  It's probably a good idea to first start with a smaller dose, e.g. 25 mg twice a day, for the first day or two to see if there are any side-effects.  I always add folate 800 mcg with any anti-depressant.  Don't forget 2-3 fish oil capsules per day unless you eat at least two fish meals a week.  If a patient responds on the low dose, there is no reason to increase to a full dose of 100 mg/day.

Nortriptyline Included in STAR*D for Treatment Resistant Depression: STAR*D will be by far the largest ever multisite, prospective, randomized, multistep clinical study of outpatients with nonpsychotic major depressive disorder comparing various treatment options for treatment resistant depression. The SSRI citalopram (Celexa) will be the level 1 treatment. For 4000 adults up to age 75, those not responding to citalopram will be randomized to sertraline, bupropion, venlafaxine, cognitive therapy, or three citalopram augment options (bupropion, buspirone, cognitive therapy). Those who receive cognitive therapy (switch or augment options) at level 2 without sufficient improvement are will be randomization to venlafaxine or bupropion (level 2a). Level 2 and 2A participants are eligible for random assignment to two switch options (mirtazapine or nortriptyline) and to two augment options (lithium or thyroid hormone) added to the primary antidepressant (citalopram, bupropion, sertraline, or venlafaxine) (level 3). Those without sufficient improvement at level 3 are eligible for level 4 random assignment to one of two switch options (tranylcypromine or the combination of mirtazapine and venlafaxine). Participants with an adequate symptomatic response may enter the 12-month naturalistic follow-up phase with brief monthly and more complete quarterly assessments.

Nortriptyline Did Better than Fluoxetine (Prozac) in Small DB: A 48-patient 6-week DB PC study of Major Depression found that nortriptyline 150 mg/d did better than fluoxetine 60 mg/d.  There was no difference in the dropout rate. Double-blind comparison of fluoxetine and nortriptyline in the treatment of moderate to severe major depression. There was no difference in QTc intervals. Akhondzadeh S, Faraji H, et al. Tehran Univ. J Clin Pharm Ther. 2003 Oct;28(5):379-84. Ed: Although this is a very small and short study, the outcome is in the expected direction since nortriptyline is more of a dual action anti-depressant, which as a group usually do better than SSRIs, except perhaps in young women.

Nortriptyline Better than Fluoxetine in Poststroke Depression: In a 12-week DB PC study with 104 stroke patients, 56 with major or minor depression, those with depression received either 25 mg/d increased to 100 mg/d of nortriptyline or 10 mg/d increased to 40 mg/d of fluoxetine or placebo. There were 50% decreases in the HAM-D depression score in 77% of nortriptyline, 14% of fluoxetine, 31% of placebo patients. Fluoxetine patients lost 15 pounds vs. no change with nortriptyline or placebo. Nortriptyline versus fluoxetine in the treatment of depression and in short-term recovery after stroke: a placebo-controlled, double-blind study. Robinson RG, Schultz SK, et al. Buenos Aires, NIMH, and the University of Iowa, Am J Psychiatry 2000 Mar;157(3):351-9. 

Nortriptyline or Venlafaxine (Effexor) Better than Fluoxetine (Prozac) for Melancholia: Two studies have found this. A third retrospective study reports that of nine patients to develop melancholia while already on anti-depressant, all were on an SSRI. They responded quickly to non-SSRI meds. Guadagno, East Tenn State U, APA 5/30/98 Toronto

Fluoxetine (Prozac) as Good as Nortriptyline in Post-Stroke Depression: In a DB PC 3 month study followed by an open 12 month study on meds, researchers found 1 nortriptyline and 1 fluoxetine relapses but 5 placebo relapses. However, after stopping the meds after the 15^th month, nortriptyline had more relapses suggesting to author that more gradual withdrawal and monitoring is necessary. Preventing poststroke depression: a 12-week double-blind randomized treatment trial and 21-month follow-up. Narushima K, Kosier JT, Robinson RG. University of Iowa, J Nerv Ment Dis 2002 May;190(5):296-303

Fluoxetine as Good as Nortriptyline: In a 5-week DB study of 204 patients with major depressive disorders, there was a 65% response rate with fluoxetine vs. a 71% rate with nortriptyline, not a significant difference. Nausea occurred more often with fluoxetine and dry mouth with nortriptyline. Comparative efficacy and safety of nortriptyline and fluoxetine in the treatment of major depression: a clinical study. Fabre LF, Scharf MB, Itil TM. J Clin Psychiatry 1991 Jun;52 Suppl:62-7

Paroxetine (Paxil) Almost as Good as Nortriptyline in Elderly: In a 12-week DB PC study of 114 elderly, the intent to treat response rates were 55% vs 57%. Completer analysis was also equal. Efficacy was same even though there were many more nortriptyline drop-outs due to side-effects: 33% vs. 16% for paroxetine. University of Pittsburgh. A twelve-week, double-blind, randomized comparison of nortriptyline and paroxetine in older depressed inpatients and outpatients. Mulsant BH, Pollock BG, et al. Am J Geriatr Psychiatry 2001 Fall;9(4):406-14. Ed: These Paxil studies were funded by the manufacturer and may exaggerate the benefits of paroxetine. In any case, nortriptyline actually worked better for those not developing excessive side-effects.  Therefore, one sensible strategy is to start with nortriptyline and switch to an SSRI if excessive side-effects occur, thus giving the best of both worlds.  However, I prefer celexa or sertraline to Paxil XR due to Paxil's much shorter half-life, withdrawal difficulties, and higher suicide rate.

Paroxetine as Good as Nortriptyline in Ischemic Heart Disease But Fewer Side-Effects: In a DB 6-week study of paroxetine 20-30 mg/d vs. nortriptyline to 50-150 ng/mL, there were 67% vs. 73% response rates by intent to treat analysis, but the side-effect dropout rates were 5% vs 25%. The authors claim that paroxetine less likely to cause cardiovascular side-effects. Treatment of major depression with nortriptyline and paroxetine in patients with ischemic heart disease. Nelson JC, Kennedy JS, et al. Am J Psychiatry 1999 Jul;156(7):1024-8. Ed: Paroxetine has fallen into disrepute due to its increased suicide rate and withdrawal problems. This Paxil funded study may have been more quick to discontinue due to nortriptyline type side-effects than Paxil type. Other research suggests similar side-effect rates, but different types of side-effects.

Paroxetine a Little Better than Nortriptyline in Elderly: In a 12-week DB study of 210 elderly with depression, paroxetine 50-150 mg/d was compared to nortriptyline 25-100 mg/d. There were 71% vs. 61% response rates with better memory, cognitive functioning, and quality of life favoring paroxetine. Comparison of sertraline and nortriptyline in the treatment of major depressive disorder in late life. Bondareff W, Alpert M, et al. USC. Am J Psychiatry 2000 May;157(5):729-36. 

Nortriptyline a Little Better than Paroxetine in Elderly: In a 6-week DB study of 80 elderly depressed with an average age of 75, the dropout rates due to side-effects were 19% vs 14%. Response rates by intent to treat 44% vs. 57%, but response rates by completers were 78% vs. 66% slightly favoring nortriptyline. Randomized comparison of nortriptyline and paroxetine in the treatment of late-life depression: 6-week outcome. Mulsant BH, Pollock BG, et al. J Clin Psychiatry 1999;60 Suppl 20:21-5

Nortriptyline Alone as Good as Nortriptyline plus Perphenazine in Elderly Psychotic Depression: In a DB PC study of 36 patients with major depression with psychotic features, both treatments were well tolerated but the 44% and 50% response rates were not significantly different. A double-blind randomized comparison of nortriptyline plus perphenazine versus nortriptyline plus placebo in the treatment of psychotic depression in late life. Mulsant BH, Sweet RA, et al. U Pitt. . . J Clin Psychiatry. 2001 Aug;62(8):597-604.

Post-Partum Depression: Nortriptyline as Good as SSRIs: In an 8-week DB study of 109 women with moderate to severe postpartum depression without another Axis I disorder, sertraline did no better than nortriptyline.  At week 4, 46% of sertraline and 56% of nortriptyline patients achieved a 50% reduction in symptoms. By 8 weeks, 94% of completers had a positive response. The number of side-effects were similar in degree, but different in type: dry mouth and constipation for nortriptyline vs. headache, perspiration, and hot flashes for sertraline. Wisner K, et al. University of Pittsburgh. J Clin Psychopharm 2006;26:353-60.

Phenelzine Did Better than Nortriptyline Maintenance for Elderly: In a DB PC study of 51 elderly with major depression, those responding to an anti-depressant were then followed on the study meds for one year. 13% of phenelzine patients relapsed, 53% of nortriptyline, and 65% of placebo. A placebo-controlled comparison of nortriptyline and phenelzine in maintenance therapy of elderly depressed patients. Georgotas A, McCue RE, Cooper TB. Arch Gen Psychiatry 1989 Sep;46(9):783-6. Ed: MAO inhibitors are underused by modern psychiatry.

Tranylcypromine Did as Well as Nortriptyline: In a short 4-week DB PC study of 122 out-patient with major depression, both medicines did equally better than placebo. Tranylcypromine vs. nortriptyline vs. placebo in depressed outpatients: a controlled trial. White K, Razani J, et al.

Venlafaxine No Better than Nortriptyline:  In a 6-month single-blind study of 68 in- and out-patients with moderate to severe unipolar major depression, the intent-to-treat remission rate was 71% with venlafaxine vs. 70% with nortriptyline. No significant differences were observed between dropout rates in the two groups. Single-blind comparison of venlafaxine and nortriptyline in elderly major depression. Gasto C, et al. University of Barcelona, Spain. J Clin Psychopharmacol. 2003 Feb;23(1):21-6.

Nortriptyline Helps Kids a Little, Loading Dose Table: In an 8-week DB PC study of 50 children ages 6-12 with chronic, severe major depression with frequent family histories of major depression and alcoholism, researchers used a 24-hr test dose loading dose strategy. Mean serum level were 90ng/mL. All were naive to tricyclics. There was a 31% nortriptyline vs 17% placebo response rate. Pharmacokinetically designed double-blind placebo-controlled study of nortriptyline in 6- to 12-year-olds with major depressive disorder. Geller B, Cooper TB, et al. Univ S. Carolina. J Am Acad Child Adolesc Psychiatry 1992 Jan;31(1):34-44

Nortriptyline No Benefit Depressed Teens: In a DB PC study of 52 teens ages 12-17 with chronic, severe depression, there were 17 who improved on placebos before the true study even began. Of the 35 in the study, only one on nortriptyline improved in 8 weeks. Double-blind placebo-controlled study of nortriptyline in depressed adolescents using a "fixed plasma level" design. Geller B, Cooper TB, Graham DL, Marsteller FA, Bryant DM. Psychopharmacol Bull 1990;26(1):85-90

Duke: Nortriptyline Used in Elderly; Switch if Anti-Cholinergic Side-Effects; Zoloft, Nortriptyline, Prozac Help Cognition: Using data from two DB 12-week studies with 444 elderly with major depression comparing sertraline, fluoxetine and nortriptyline, improved depression and a lower anticholinergic side effect (dry mouth and constipation) severity were associated with statistically significant improvement in cognition. The correlations between improvements in depression and improvement in tested cognitive function were highest for sertraline followed by nortriptyline and then fluoxetine. Does antidepressant therapy improve cognition in elderly depressed patients? Doraiswamy PM, et al. Duke University. . J Gerontol A Biol Sci Med Sci. 2003 Dec;58(12):M1137-44.

Harvard: Nortriptyline Looks Good for Treatment Resistant Depression Except for Avoidant Personalities: In a report of 92 adults with treatment-resistant major depression and treated for 6 weeks in an open trial with nortriptyline, the presence of avoidant personality disorder (p <.01) predicted poorer response to nortriptyline. The response rate was 17% for patients with and 49% for patients without comorbid avoidant personality disorder. No other comorbid diagnoses were found to predict clinical response in a statistically significant manner. Psychiatric comorbidity as a predictor of clinical response to nortriptyline in treatment-resistant major depressive disorder. These researchers concluded, "Nortriptyline should be considered as potential treatment if patients fail to respond to other antidepressants." Papakostas GI, et al. Massachusetts General-Harvard. . J Clin Psychiatry. 2003 Nov;64(11):1357-61. Lithium didn't help 35 who didn't respond to nortriptyline in a subsequent DB PC trial. J Clin Psychopharmacol. 2003 Feb;23(1):92-5.

University of Pittsburgh: Nortriptyline Considered a Standardized Treatment for Elderly Depression: Helps Both Depression and Anxiety: Analyzing data from a 12-week DB PC study comparing nortriptyline and paroxetine in 116 elderly with depression and in an open trial with 125 more, anxious and nonanxious groups did not differ in terms of response rates, time to response, dropout rates, or time to dropout. Side effects declined more quickly and more significantly in the anxious group than in the nonanxious group. Good treatment outcomes in late-life depression with comorbid anxiety. Lenze EJ, et al. University of Pittsburgh. . J Affect Disord. 2003 Dec;77(3):247-54.

Nortriptyline Helps Tinnitus With Depression: In a DB PC study of 91 patients with tinnitus and MDD or lesser depression, those treated with nortriptyline to 50-150 ng/mL had tinnitus decreased by 31% in loudness. Depression decreased as well. U Washington. A randomized trial of nortriptyline for severe chronic tinnitus. Effects on depression, disability, and tinnitus symptoms. Sullivan M, Katon W, Russo J, Dobie R, Sakai C. Arch Intern Med 1993 Oct 11;153(19):2251-9

ECT High Relapse Rate, Lithium-Nortriptyline Helped Some: In an open study of 290 MDD referred and treated with ECT, 159 remitted. 88 were put in a DB PC study with nortriptyline vs. lithium-nortriptyline vs. placebo. Over the 24-week trial, the relapse rate for placebo was 84% vs. 60% for nortriptyline, and 39% for nortriptyline-lithium, 39%, a statistically significant difference. All but 1 instance of relapse with nortriptyline-lithium occurred within 5 weeks of ECT termination. Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: a randomized controlled trial. Sackeim HA, Haskett RF, et al. New York State Psychiatric Institute, JAMA 2001 Mar 14;285(10):1299-307.

ECT High Relapsed Helped Some by Meds: 84 patients responding to ECT DB PC nortiptyline or nortriptyline + lithium at 0.5-0.9 mEq/L. At 6 months, 84% placebo relapsed, 60% nortriptyline relapsed, and 39% lithium + nortriptyline relapsed. The form of ECT and the number of treatments had no impact on relapse. These may have been refractory patients. Sackeim, JAMA 01;285:1299

ECT Relapse Nortriptyline > Nortriptyline + Perphenazine: 28 psychotic depressed had ECT. Those on nortriptyline alone to prevent relapse did non-significantly better and had fewer side-effects. Continuation treatment of delusional depression in older adults. Meyers BS, Klimstra SA, et al. Am J Geriatr Psychiatry 2001 Fall;9(4):415-22

Nortriptyline Didn’t Help Prevent Post Partum: In a DB PC study of 51 patients with a history of post-partum depression, 6 relapsed on nortriptyline and 6 on placebo. Case Western. Prevention of recurrent postpartum depression: a randomized clinical trial. Wisner KL, Perel JM, Peindl KS, Hanusa BH, Findling RL, Rapport D. J Clin Psychiatry 2001 Feb;62(2):82-6

Med & Bereavement Therapy Best: 80 patients over age 49 were randomized to 16 weeks of DB nortriptyline and/or interpersonal psychotherapy and/or placebo. The combination worked best although only slightly better than the medication alone. Charles Reynolds III, Am J Psychiatry 2/99 156:202-8

Nortriptyline and Interpersonal Therapy Better than Either Alone: 187 elderly over age 60 in a DB study were treated with Nortriptyline to 80-120 ng/mL with or without interpersonal psychotherapy vs placebo. JAMA 1/6/99;281:39. The combo did best. There was a 20% recurrence in 3 years with the combination treated vs. 43% with Nortriptyline, 60% with IPT, and 90% with placebo. Half of nortriptyline relapses had stopped nortriptyline. Most relapses occurred in the first year (44/59).

Nortriptyline Appeared to Help ADHD Kids: 6 week open trial followed by placebo substitution in some. Robust decrease in ADHD and oppositionality in open trial and relapse with placebo. MGH (poor study design). Some wt gain. A controlled study of nortriptyline in children and adolescents with attention deficit hyperactivity disorder. Prince JB, Wilens TE, Biederman J, Spencer TJ, Millstein R, Polisner DA, Bostic JQ. J Child Adolesc Psychopharmacol 2000 Fall;10(3):193-204

Helped Depressed Diabetics but not Fasting Blood Sugar: In a study of 68 diabetic patients in poor control and 28 with major depression using a DB PC methodology with half receiving nortriptyline, depression improved but not blood sugar control due to direct adverse effect of nortriptyline offsetting increased compliance by the less depressed patients. Lustman, Wash U, Psychosom Med 5/97 59:241.

Nortriptyline Helped Elderly Bereaved More Than Interpersonal: 80 patients with major depression following the death of a spouse were treated in DB PC 16-week study with an added 16 weeks of DB for responders. Remission occurred in 69% with nortriptyline + interpersonal therapy, 56% with nortriptyline + a medical clinic group, 29% with interpersonal therapy alone, and 45% with the medical clinic group. The average dose were 60-65 mg/day. Univ. Pittburgh, Amer J Psych 99;155:202. Only dru mouth and an increased heart rate were found more often with nortriptyline than placebo. Physical tiredness, daytime sleepiness and nocturnal sleep disturbance were related primarily to residual depression rather than treatment with nortriptyline. Int J Geriatr Psychiatry. 1999 Dec;14(12):1014-8. 

Treatment Range 80-150 ng/ml: Higher or lower do worse. DB. Sorensen, Psychopharm 2/75

80-120 ng/mL as Good or Better than 40-60 ng/mL in Elderly: In a 3 year DB follow-up study of 41 elderly treated with different levels of nortriptyline, researchers found slightly more constipation with higher dose but slightly fewer symptoms of depression and non-significantly fewer relapses. Three-year outcomes of maintenance nortriptyline treatment in late-life depression: a study of two fixed plasma levels. Reynolds CF 3rd, Perel JM, et al. Am J Psychiatry. 1999 Aug;156(8):1177-81.

Long-term Nortriptyline Maintenance Recommended for Elderly Over Age 70 by University of Pittsburgh: The authors compared response rates, by age (60-69 vs. 70+), to acute, continuation, and 1-year maintenance depression treatment. Patients (N = 180) received open combined treatment with nortriptyline (NT)/placebo and interpersonal psychotherapy (IPT). Patients who recovered then entered randomized, double-blind maintenance treatment with NT or placebo or received maintenance monthly IPT (combined with NT or placebo). Comparison of time-to-remission and recovery and absolute rates of remission, relapse, recovery, and recurrence yielded similar times to/rates of remission and recovery; however, older patients had far more recurrence during the first year of maintenance therapy. Although responses to acute and continuation treatment with combined NT and psychotherapy were similar, the older group had more recurrence in the first year of maintenance. Continuation of combined medication and psychotherapy may represent the best long-term treatment. Treatment of 70(+)-year-olds with recurrent major depression. Excellent short-term but brittle long-term response. Reynolds CF 3rd, et al. University of Pittsburgh. Am J Geriatr Psychiatry. 1999 Winter;7(1):64-9. . 

Treatment Resistant Depression in the Elderly: Continued Efforts May be of Value: In a study of 53 elderly with major depressive disorder who failed treatment with paroxetine plus interpersonal psychotherapy, they were given 1 to 3 open trials of augmentation with bupropion sustained release, nortriptyline, or lithium. Successively fewer subjects entered each sequential trial of augmentation since many responded to the earlier treatment(s). Twelve subjects subsequently received venlafaxine XR monotherapy. Sixty percent of subjects responded to some form of augmentation, with 45% (24/53), 31% (5/16), and 43% (3/7) responding to the first, second, and third augmentation trials, before getting to venlafaxine. The mean time to response after starting the first augmentation trial was 6.0 weeks. Forty-two percent (N = 5) of the venlafaxine XR-treated subjects responded with the mean time to response of 6.4 weeks. Geriatric depression treatment in nonresponders to selective serotonin reuptake inhibitors. Whyte EM, et al. University of Pittsburgh. . J Clin Psychiatry. 2004 Dec;65(12):1634-41. Ed: This was a very small study and not double-blind or controlled, so very susceptible to observer bias. The University of Pittsburgh has recently received extensive funding from the manufacturers of Paxil and Effexor XR, but also has a very long history, predating this funding, of researching depression treatment in the elderly, especially with nortriptyline and lithium.  The main message of this study is "Don't give up." None of the augmentation or substitution strategies looks clearly superior nor is there any evidence that continuing patients on paroxetine was of any value.

Single 48 hour Blood Test Recommended: 20 routine patients with endogenous depression were investigated in a kinetic and 4 week treatment study. Steady-state plasma nortriptyline concentrations above 200 microgram/L were associated with a highly significant poorer therapeutic outcome. The correlations between the 24, 48 and 72 hour concentrations and steady-state concentration were very good (r = 0.81, 0.97, 0.94; p less than 0.0001) Dosage adjustment from simple nortriptyline spot level predictor tests in depressed patients. Montgomery SA, McAuley R, Montgomery DB, Braithwaite RA, Dawling S. Clin Pharmacokinet. 1979 Mar-Apr;4(2):129-36

Routine Blood Tests for Tricyclic Discouraged: "The range of tricyclic antidepressant plasma levels (or doses) needed for therapeutic response remains largely unresolved, since plasma- or dose-response relationships have not been clearly defined for either therapeutic or nontherapeutic effects. The fact that certain patients apparently became more depressed at higher plasma levels must be balanced against the facts that "depression" is a mixture of disorders as yet poorly distinguishable and that tricyclic antidepressants have multiple pharmacologic effects. There is presently no justification for routinely monitoring tricyclic antidepressant plasma levels, even though, as for any drug, such determinations are justifiable in patients who are unresponsive or show signs of toxicity. Plasma level determinations can never replace sound clinical judgment and dosage adjustment for individual patients." The role of plasma concentrations in the use of tricyclic antidepressant drugs. Levine RR. Boston University. Prog Neuropsychopharmacol. 1979;3(1-3):211-22

Recommendations on When to Get Blood Tests: "With amitriptyline and nortriptyline there is good evidence for a 'therapeutic window' within which maximum antidepressant action is obtained. Many patients being treated with these drugs have plasma levels outside recommended therapeutic ranges. Experience in our department has shown that there are a number of clinical situations where routine plasma level monitoring of selected antidepressants is of value: (1) inadequate clinical response; (2) side-effects/toxicity; (3) complicating medical conditions; (4) suspected poor compliance; and (5) long-term therapy." The role of plasma level monitoring of tricyclic antidepressant drugs as an aid to treatment. Braithwaite R. Ciba Found Symp. 1979;(74):167-97

Started at 75-125 mg HS Without Difficulty: Open trial 26 in-patients dose depending on weight. 81% reached therapeutic level within a week. Two orthostatic hypotension was treated with fludrocortisone. There was a 45% decrease in HAM-D depression scores the first week. High initial nortriptyline doses in the treatment of depression. Warner MD, Griffin M, Peabody CA. Baylor University. J Clin Psychiatry 1993 Feb;54(2):67-9

Nortriptyline Might be Less Helpful for Avoidant Personality Depression: In a small open trial of 92 treatment resistant major depression patients, 42% of patients improved while on nortriptyline.  Those who had an Avoidant Personality diagnosis had only 17% improving while on nortriptyline vs. 48% for all other patients. Psychiatric comorbidity as a predictor of clinical response to nortriptyline in treatment-resistant major depressive disorder. Papakostas GI, Petersen TJ, et al. Harvard. J Clin Psychiatry. 2003 Nov;64(11):1357-61. Ed: This is one of the rare open trial studies that might have been worth publishing.  Still, the Harvard psychiatrists were wrong to claim that 42% "responded to nortriptyline," implying that nortriptyline helped all of these patients.  Some of these, however, would have improved on placebo and did not improve due to the nortriptyline.  The proper wording would be that the "responded while on nortriptyline." Harvard also makes the foolish mistake of reporting their results to the tenth of a percent (which I eliminated), implying a much higher degree of precision than is possible with only 92 patients. 

Other Uses of Nortriptyline:

Nortriptyline Favored for Smoking Abstinence: In a review of randomized trials in which nortriptyline was compared to placebo or bupropion hydrochloride SR for at least 6-month prolonged abstinence, confirmed with a biochemical test, five randomized trials, including 861 smokers, found that nortriptyline resulted in significantly higher prolonged abstinence rates after at least 6 months [relative risk (RR) = 2.4]. The difference in efficacy between nortriptyline and placebo decreased over time. Although bupropion resulted in higher abstinence rates compared with nortriptyline, the difference was not statistically significant (RR = 1.7). Nortriptyline for smoking cessation is well tolerated and safe. Authors concluded that health care professionals should be recommended to prescribe nortriptyline as a first-line therapy for smoking cessation, also because of the much lower cost of nortriptyline compared to bupropion SR. Should nortriptyline be used as a first-line aid to help smokers quit? Results from a systematic review and meta-analysis. Wagena EJ, et al. Maastricht University, The Netherlands. . Addiction. 2005 Mar;100(3):317-26.

Nortriptyline Most Cost Effective for Pain Control of Antidepressants and Antiepileptics: These groups of drugs modulate pain transmission by interacting with specific neurotransmitters and ion channels. Tricyclic antidepressants (e.g., amitriptyline, nortriptyline, desipramine) and other antidepressants (i.e., bupropion, venlafaxine, duloxetine) are effective in the treatment of neuropathic pain independent of their antidepressant effect This is strongest in agents with mixed-receptor or predominantly noradrenergic activity, rather than serotoninergic activity. First-generation antiepileptic drugs (i.e., carbamazepine, phenytoin) and second-generation antiepileptic drugs (e.g., gabapentin, pregabalin) are effective in the treatment of neuropathic pain. Tricyclics are the most cost-effective agents. Second-generation antiepileptic drugs are associated with fewer safety concerns in elderly patients. Tricyclic antidepressants have modest efficacy in the treatment of fibromyalgia and chronic low back pain. Duloxetine and pregabalin also have modest efficacy in patients with fibromyalgia. Antidepressants and antiepileptic drugs for chronic non-cancer pain. Maizels M, et al. Kaiser Permanente, Woodland Hills, California. . Am Fam Physician. 2005 Feb 1;71(3):483-90. Ed: Amitriptyline causes too much weight gain. Desipramine has a low safety index, i.e., it is the most fatal in overdoses with amitriptyline intermediate. Nortriptyline causes less dry mouth, fewer cardiac concerns, no weight gain, and has a high safety index.

Nortriptyline or Fluoxetine Help Stroke Victims Live Longer: Poststroke depression increases mortality for more than 5 years after the stroke. In a 12-week DB PC study with 9 years of follow-up for 104 stroke patients treated with nortriptyline, fluoxetine, or placebo early in the recovery period after a stroke, 48% had died by the time of the 9-year follow-up. Of 53 patients who were given full-dose antidepressants, 68% were alive at follow-up, compared with only 36% of placebo-treated patients, a significant difference. The beneficial effect of antidepressants remained significant both in patients who were depressed and in those who were nondepressed at enrollment, after the effects of other factors associated with mortality (i.e., age, coexisting diabetes mellitus, and chronic relapsing depression) were controlled. There were no intergroup differences in severity of stroke, impairment in cognitive functioning and activities of daily living impairment, and other medications received. Mortality and poststroke depression: a placebo-controlled trial of antidepressants. Jorge RE, et al. University of Iowa. Am J Psychiatry. 2003 Oct;160(10):1823-9.

Nortriptyline as Good as Narcotics for Postherpetic Neuralgia: In a DB PC crossover study of 76 patients with postherpetic neuralgia, morphine 91 mg or methadone 15 mg did no better than nortriptyline 89 mg or desipramine 63 mg. Opioids and tricyclics (TCA) reduced pain (1.9 and 1.4) more than placebo (0.2; p < 0.001). A small trend favoring opioids over TCA fell short of significance (p = 0.06), and reduction in pain with opioids did not correlate with that following TCA. Treatment with opioids and TCA resulted in greater pain relief (38 and 32%) compared with placebo (11%; p < 0.001). More patients completing all three treatments preferred opioids (54%) than TCA (30%; p = 0.02). Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial. Raja SN, et al. Johns Hopkins. . Neurology. 2002 Oct 8;59(7):1015-21. Ed: Nortriptyline is much preferred over desipramine both because nortriptyline is much better researched for pain relief and has a much higher safety index in overdose. Nortriptyline plus a non-narcotic pain relievers would undoubtedly have been far superior to a narcotic by itself and very likely just as good as the narcotic with a non-narcotic pain reliever.  It borders on medical malpractice to give opiates for PHN, since PHN is a temporary condition, the narcotics are obviously unnecessary, and the narcotics too often lead to serious addiction problems. 

Thomas E. Radecki, M.D., J.D.

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