(British Approved Name Modified, US Adopted Name, rINN)

International Nonproprietary Names (INNs) in main languages (French, Latin, and Spanish):

Pharmacopoeias. In Europe, Japan, and US.

European Pharmacopoeia, 6th ed. (Nortriptyline Hydrochloride). A white or almost white powder. Sparingly soluble in water soluble in alcohol and in dichloromethane. Protect from light.

The United States Pharmacopeia 31, 2008 (Nortnptyline Hydrochloride). A white to off-white powder having a slight characteristic odour. Soluble 1 in 90 of water, 1 in 30 of alcohol, 1 in 20 of chloroform, and 1 in 10 of methyl alcohol practically insoluble in ether, in benzene, and in most other organic solvents. pH of a 1% solution in water is about 5. Store in airtight containers. Protect from light.

Adverse Effects, Treatment, and Precautions

As for tricyclic antidepressants in general (see Amitriptyline).

Breast feeding. For comments on the use of tricyclic antidepressants in breast feeding patients, see under Precautions for Amitriptyline.

Effects on ventilation. Severe hyperventilation developed in a 61-year-old man with end-stage renal disease after receiving nortriptyline 125 mg daily mechanical ventilation was necessary to correct severe respiratory alkalosis.

Porphyria. Nortriptyline is considered to be unsafe in patients with porphyria although there is conflicting experimental evidence of porphyrinogenicity.

Interactions

For interactions associated with tricyclic antidepressants, see Amitriptyline.

Pharmacokinetics

Nortriptyline is the principal active metabolite of amitriptyline. Nortriptyline has been reported to have a longer plasma half-life than amitriptyline. Nortriptyline is subject to extensive first-pass metabolism in the liver to 10-hydroxynortriptyline, which is active.

Metabolism. Individuals with a poor debrisoquine hydroxylation phenotype may be at greater risk of confusional states when taking nortriptyline. This was thought to be because the polymorphic hydroxylation of debrisoquine and nortriptyline are mediated by similar enzymatic mechanisms [the cytochrome P450 isoenzyme CYP2D6], with poor oxidisers having higher plasma nortriptyline concentrations. A nonlinear (dose-dependent) relationship between dose and plasma-nortriptyline concentrations has been observed during therapeutic drug monitoring in subjects who were considered to be extensive metabolisers of debrisoquine nonlinearity did not appear to occur in poor metabolisers. There was no significant correlation between hydroxylation phenotype and amitriptyline concentrations, suggesting that demethylation and hydroxylation of tricyclic antidepressants are mediated by different cytochrome P450 isoen-zymes.

The pharmacokinetics and pharmacological actions of 10-hydroxynortriptyline, the major active metabolite of nortriptyline, have been reviewed.

Therapeutic plasma concentrations. Nortriptyline appears to have an optimum antidepressant effect at plasma concentrations between 50 and 150 nanograms/mL. Outside this range, there is a poor clinical response. Plasma concentration measurements are unequivocally useful in problem patients who do not respond to usual oral doses or in high-risk patients for whom, because of age or medical illness, it is especially important to use the lowest possible effective dose of the drug.

It has been suggested that within this window of total nortriptyline concentrations there is a probability of an antidepressant response of 68% or more with free concentrations of 7 to 10 nanograms/mL.

For reference to dose-dependent kinetics of nortriptyline observed in individuals with an extensive debrisoquine hydroxylation phenotype, see under Metabolism, above.

Uses and Administration

Nortriptyline is a dibenzocycloheptadiene tricyclic antidepressant with actions and uses similar to those of amitriptyline. It is the principal active metabolite of amitriptyline. Nortriptyline is one of the less sedating tricyclics and its antimuscarinic effects are mild.

Nortriptyline is given orally as the hydrochloride although doses are expressed in terms of the base nortriptyline hydrochloride 113.8 mg is equivalent to about 100 mg of nortriptyline. In the treatment of depression a low starting dose is given gradually increasing to the equivalent of 75 to 100 mg daily in 3 or 4 divided doses. Up to a maximum of 150 mg daily may be required in patients with severe depression. Licensed drug information recommends that plasma concentrations of nortriptyline should be monitored when doses above 100 mg daily are given however, the BNF considers that the evidence of any practical value is uncertain. Adolescents and the elderly may be given 30 to 50 mg daily in divided doses. Since nortriptyline has a prolonged half-life, once-daily dosage regimens are also suitable, usually given at night.

Nortriptyline is also used for the treatment of nocturnal enuresis in children in whom organic pathology has been excluded. However, drug therapy for nocturnal enuresis should be reserved for those in whom other methods have failed and should preferably only be given to cover periods away from home tricyclic antidepressants are not recommended in children under 6 years of age (the BNF recommends that they should notbe given until 7 years of age). Suggested doses are:

• 10 mg for children aged 6 to 7 years (20 to 25 kg)

• 10 to 20 mg for children aged 8 to 11 years (25 to 35 kg)

• 25 to 35 mg for children aged over 11 years (35 to 54 kg)

The dose should be given 30 minutes before bedtime and treatment, including a period of gradual withdrawal, should not continue for longer than 3 months. A full physical examination is recommended before a further course.

Nortriptyline should be withdrawn gradually to reduce the risk of withdrawal symptoms.

Pain. Antidepressants, usually amitriptyline or another tricyclic, are useful in alleviating some types of pain (see Choice of Analgesic). Nortriptyline has also been tried and may produce fewer adverse effects than amitriptyline. An initial oral dose of 10 to 25 mg at night has been suggested by the BNF for the management of neuropathic pain. References to the use of nortriptyline.

Smoking cessation. For reference to the use of nortriptyline in management of smoking cessation, see under Amitriptyline.

Preparations

BP 2008: Nortriptyline Capsules Nortriptyline Tablets

The United States Pharmacopeia 31, 2008: Nortriptyline Hydrochloride Capsules Nortriptyline Hydrochloride Oral Solution.

Proprietary Preparations

Argentina: Ateben

Australia: Allegron

Austria: Nortrilen

Belgium: Nortrilen

Brazil: Nortrip Pamelor

Canada: Aventyl Norventyl

Czech Republic: Nortrilen

Denmark: Noritren

Finland: Noritren

Germany: Nortrilen

Greece: Nortrilen

Hong Kong: Nortrilen

India: Sensival

Israel: Nortylin

Italy: Noritren

The Netherlands: Nortrilen

Norway: Noritren

New Zealand: Norpress

Portugal: Norterol

Spain: Norfenazin Paxtibi

Sweden: Sensaval

Switzerland: Nortrilen

Thailand: Norline Nortrilen Nortyline Ortrip

United Kingdom: Allegron

USA: Aventyl Pamelor

Multi-ingredient

Argentina: Karile

Chile: Notitrel

Indonesia: Notival

Ireland: Motival

Italy: Dominans

Mexico: Notival

South Africa: Notival

Spain: Tropargal

Thailand: Cetavol

United Kingdom: Motival.

Answer. Your story, unfortunately, echoes those of millions of individuals who suffer from severe, major depression. Some day, you may look back at what happened following your suicide attempt and feel that you were given a second chance to succeed at life. While I don’t have any magic solutions for you, I do want to offer you the perspective I have gained after having treated many hundreds of such patients.

First: Depression is a treatable and reversible condition, even when several therapies or medications have failed. There are still many treatments that could be tried and which I have seen work. It might be frustrating, but not all treatments are beneficial to an individual patient. You should talk to your psychiatrist about both your ongoing feelings of hopelessness and possible trials on some of the newer antidepressants, such as Effexor and Remeron. And, whatever you may have heard about ECT (electroconvulsive therapy), do not exclude this as a treatment option! I have seen ECT work for people who were virtually at death’s door. It is safe and very effective.

Second: In all my years of treating depressed patients and working with their families, I have never seen a single instance in which the family truly felt they would be better off without their depressed family member. That’s right, not once. This belief is virtually always a symptom of severe depression. In fact, suicide is usually a devastating emotional blow to a family, from which recovery is extremely difficult. Some families never recover from losing a loved one in this way.

Third: You are not alone. If you have not yet joined the National Depressive and Manic Depressive Association (NDMDA), I would urge you to do so. They provide support and peer counseling for thousands of individuals with depression; you can call 800-826-3632 for local referrals. You can also contact the National Mental Health Self-help Clearinghouse (800-553-4539). These groups should supplement, not replace, the help you are already receiving. Also keep in mind that the Samaritans provide 24-hour anonymous telephone counseling for suicidal individuals (ask your telephone operator for the number).

Finally, depending on your spiritual and religious orientation, consider some form of pastoral counseling; not as a replacement, but as a supplement to your therapy. I know it may be hard for you to believe there is a light at the end of the tunnel, but I hope you can believe that I believe that. Good luck…

Answer. The short, no-frills answer to your question is that any of the major antidepressants or anxiolytics are probably safe, now that the most vulnerable period of organ-formation (the first trimester) has passed. I see no reason why Zoloft and/or Klonopin could not be restarted, if the clinical situation is severe enough to warrant the modest risks. An OB/GYN consult is always a reasonable precaution, but I would not necessarily be governed by it, if you believe your patient must be on a medication. If you care to read on, here is the more complicated story:

With respect to antidepressants (ADs) in pregnancy, most data come from studies of tricyclics and fluoxetine(Prozac); we have only a modicum of information about newer agents such as sertraline (Zoloft), paroxetine (Paxil), venlafaxine (Effexor) and nefazodone (Serzone). The tricyclics (e.g., desipramine (Norpramin), imipramine (Tofranil), nortriptyline (Pamelor)) appear to have little potential for teratogenicity. Similarly, a recent study by Pastuszak and colleagues (1993) found no evidence of teratogenicity in 128 women taking fluoxetine during the first trimester, when compared to matched controls. While there was a trend toward higher miscarriage rates in the fluoxetine group compared to controls taking known non-teratogens, the risk was small (relative risk, 1.9) and comparable to that of tricyclics. (Interestingly, depression itself may also raise the risk of miscarriage). A recent study by Chambers et al. (New England Journal of Medicine 1996, vol. 335, pp. 1010-1015) found no significant differences between fluoxetine-treated pregnant women and controls in spontaneous pregnancy loss or major structural anomalies; however, the incidence of three or more minor anomalies was significantly higher in the fluoxetine cohort.

This study has been widely criticized, however, on a number of methodologic grounds. The more anticholinergic tricyclics (e.g., amitriptyline, doxepin) can occasionally induce fetal tachyarrythmias, urinary retention or intestinal obstruction. Clomipramine (Anafranil), a tricyclic used mainly in the treatment of obsessive-compulsive disorder, also has substantial anticholinergic effects, and would be expected to produce similar effects in the neonate. Wisner et al (1993) found that the doses of tricyclic antidepressant required to achieve remission actually increased during the second half of pregnancy, reaching 1.6 times the mean dose required when the patients were not pregnant. This was attributed, in part, to enhanced hepatic metabolism of antidepressants during pregnancy and to increased volume of distribution. Neonatal irritability, tachypnea, tremor and hypotonia may result from either tricyclic toxicity or withdrawal. It is therefore prudent to monitor maternal blood levels of tricyclics throughout pregnancy and gradually to reduce the dosage during the week before delivery.

Little is known about the excretion of antidepressants into breast milk or the effects of this on the nursing infant. Some studies indicate that several antidepressants or their metabolites can accumulate in breast milk, possibly peaking at about 4-6 hours after an oral dose. (See the review by Wisner et al. in the September 1996 issue of the American Journal of Psychiatry). It is not clear to what extent antidepressants accumulate in the blood of the nursing infant or whether significant adverse effects result from such accumulation. Wisner et al. (1996) conclude that sertraline is a good choice, with respect to breast-feeding. However, many clinicians feel that breast-feeding is best avoided when the mother is taking antidepressants postpartum.

Miller (1994) concluded that the tricyclics of choice during pregnancy are desipramine and nortriptyline, due to the comparative wealth of data about them, the ability to monitor serum levels and a favorable side effect profile. Alternatively, fluoxetine (Prozac) may be a reasonable choice for the pregnant patient with major depression, in light of the data from Pastuszak et al. Finally, the clinician should keep in mind that ECT appears to be a safe and effective alternative for the pregnant patient with severe depression.

With respect to benzodiazepines (BZDs): In the 70s and 80s, diazepam (Valium) was found to be associated with cleft lip and palate in the fetus and other benzodiazepines were suspected of this association. More recently, one Swedish group has linked maternal use of benzodiazepines during pregnancy with both impaired intrauterine growth and various dysmorphic birth defects. A recent review concluded that the available data indicate a positive association between first-trimester in utero exposure to benzodiazepines and a specific anomaly oral cleft.

Diazepam may double the risk of oral cleft, while alprazolam may increase the risk by more than 11-fold. However, most available data suggest that BZDs do not markedly increase the absolute risk of cleft palate or other congenital abnormalities in exposed fetuses. Thus, the baseline risk of cleft palate is about 6 in 10,000. With alprazolam exposure during the first trimester, the risk may rise to 7 in 1000, still less than 1%. The teratogenicity of lorazepam (Ativan) is less clear. Clonazepam (Klonopin) has not been evaluated for teratogenesis in controlled studies of human subjects; however, based on animal data, clonazepam seems to have low teratogenic potential (Altshuler et al, 1996) . The presence of alcohol and other substance abuse in pregnant women using benzodiazepines complicates interpretation of the data. Infants exposed to BZDs either in the last trimester or at the time of parturition may show muscular hypotonicity, failure to feed, impaired temperature regulation, apnea and low Apgar scores). The data on behavioral teratogenicity and developmental delay are inconclusive.

There is also some evidence that benzodiazepines may increase duration of labor and lead to prolonged withdrawal symptoms in the neonate, when mothers have been maintained on these agents throughout pregnancy. Withdrawal effects may be more likely when high doses of short-acting benzodiazepines have been used. Benzodiazepines should not be stopped suddenly during pregnancy, rather, tapered slowly as delivery approaches. The non-benzodiazepine anxiolytic buspirone (BuSpar) has been shown to increase the number of stillbirths in rats, when given in high doses; however, there are insufficient data in humans to determine the risks of buspirone during pregnancy.

While there is evidence that several benzodiazepines (e.g., diazepam, lorazepam, oxazepam) are excreted into breast milk, the actual levels of BZDs detected in breast milk seem to be fairly low and the consequent risk to the infant, quite small. Lorazepam seems to have minimal accumulation in the fetus and the percentage of the maternal dose of lorazepam to which a nursing infant is exposed is roughly 2.2%. Thus, use of low dose lorazepam in the nursing mother – particularly on a prn, or short-term basis – is probably safe for the infant. The excretion of buspirone into human breast milk has not been adequately studied.

Given the above risks, are benzodiazepines contraindicated during pregnancy? There is no absolute contraindication. Rather, the modest risks of BZD exposure must be weighed against the severity of the patient’s condition; the risks of no medication; and the risks of alternative medications. For example, inadequately treated panic attacks may themselves pose a risk to the fetus. Tricyclic antidepressants, fluoxetine and perhaps other SSRIs, may be reasonable alternatives to benzodiazepines for the treatment of panic disorder during pregnancy . Cognitive-behavioral therapy (CBT) may also be helpful in a variety of anxiety disorders and may reduce the need for psychotropics during pregnancy.

Answer. I am providing you with a list of commonly used antidepressants, as well as their usual doses:

Maintenance Dosage and Tablet Size for Non-MAOI Antidepressants

With respect to non-addictive medications for anxiety, it is first important to realize that the term addiction is defined in many ways. The medications most commonly used in the treatment of anxiety – the benzodiazepines, such as Valium, Librium, Ativan, etc. – are not highly addictive for the vast majority of people who are prescribed them for the right reasons. These agents may be abused or become habit-forming, however, in individuals with a history of alcohol and substance abuse, and, very rarely, in individuals who do not have such problems. The antianxiety agent buspirone (BuSpar) is a good alternative, and is not habit-forming or prone to abuse; however, while buspirone is useful for generalized anxiety, it is not helpful for panic attacks or obsessive-compulsive states.

Sometimes, low doses of the older tricyclic agents, such as doxepin 15-25 mg/day, may be useful for generalized anxiety in patients who are not good candidates for benzodiazepines. If you want more details about available medications for mood and anxiety disorders, you may want to call the NIMH Depression Awareness program.

Answer. By now, it may feel you have been tried on everything, but there are, indeed, many possibilities on the horizon. However, there is much that I don’t know about you or your history, so let’s back up about five steps. First of all, when patients with depression seem to be refractory (resistant) to treatment, the diagnosis needs to be re-examined. Could there be other factors contributing to the resistance? Could the patient have bipolar depression, that is part of a manic-depressive picture? A temporary euphoria sometimes points to a genetic kinship with bipolar disorder and might point toward the use of a mood-stabilizer. Could there be medical factors (such as low thyroid function, or low levels of vitamins B-12 or folate), or other physical illness? Is there any use of alcohol or other drugs that may be a factor?

After all these issues are sorted out, it is necessary to look at the dosages and/or blood levels of the antidepressants the person has taken, in your case, only the Pamelor has well-established blood levels associated with therapeutic response. Were you able to get up to therapeutic doses on the various medications you’ve taken, or did side effects prevent adequate trials? Were attempts made to control the side effects (e.g., yogurt or lactobacillus may sometimes help with Prozac-induced diarrhea). Next, we look at augmenting strategies (e.g., combining Prozac or Zoloft with a tricyclic, Ritalin, lithium, or thyroid hormone). You did not mention any MAOI trials; these are special antidepressants that can be very helpful when others have failed, but do require a special diet. The new antidepressant mirtazapine (Remeron) works by a special mechanism, and may be helpful in refractory cases.

Finally, are you involved in psychotherapy? I think this is a very important adjunct to antidepressant medication. Well, I hope some of this is useful. If not, I would strongly urge you to discuss with your doctor the possibility of setting up a psychopharmacology consultation for you at a medical center that specializes in mood disorders. Good luck!