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تعداد آیتم قابل مشاهده باقیمانده : -8 مورد

Nortriptyline: Drug information

Nortriptyline: Drug information
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For additional information see "Nortriptyline: Patient drug information" and "Nortriptyline: Pediatric drug information"

For abbreviations, symbols, and age group definitions show table
ALERT: US Boxed Warning
Suicidality in children and adolescents:

Antidepressants increased the risk compared with placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of nortriptyline or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared with placebo in adults older than 24 years; there was a reduction in risk with antidepressants compared with placebo in adults 65 years and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Appropriately monitor patients of all ages who are started on antidepressant therapy and observe them closely for clinical worsening, suicidality, or unusual changes in behavior. Advise families and caregivers of the need for close observation and communication with the health care provider. Nortriptyline is not approved for use in pediatric patients.

Brand Names: US
  • Pamelor
Brand Names: Canada
  • APO-Nortriptyline [DSC];
  • Aventyl
Pharmacologic Category
  • Antidepressant, Tricyclic (Secondary Amine)
Dosing: Adult

Note: In patients sensitive to adverse effects, some experts suggest lower starting doses of 10 mg daily and gradual titration (eg, at intervals ≥1 week) unless otherwise specified (Ref).

Cyclic vomiting syndrome, moderate to severe, prevention

Cyclic vomiting syndrome, moderate to severe, prevention (alternative agent) (off-label use):

Note: May be used as an alternative to amitriptyline to minimize adverse effects. Use and dosing established with amitriptyline; nortriptyline doses are equivalent (Ref).

Oral: Initial: 10 to 25 mg once daily at bedtime; may increase dose based on response and tolerability in increments of 10 to 25 mg at weekly intervals up to 100 mg/day (Ref). Typically requires a trial of 1 to 2 months at a therapeutic dose to adequately assess efficacy (Ref).

Functional dyspepsia

Functional dyspepsia (alternative agent) (off-label use):

Note: May be used to augment or replace proton pump inhibitor therapy in partial and nonresponders who have been tested for H. pylori and treated if positive (Ref). Use and dosing established with amitriptyline; nortriptyline doses are equivalent (Ref).

Oral: Initial: 10 to 25 mg once daily at bedtime; may increase dose based on response and tolerability in increments of 10 to 25 mg at ≥1-week intervals, up to a maximum of 50 mg/day (Ref). Some experts suggest a lower maintenance dose range of 20 to 30 mg/day. Typically requires a trial of 8 to 12 weeks at a therapeutic dose to adequately assess efficacy. If effective, reassess at 6 months and consider tapering; may resume if dyspepsia recurs (Ref).

Headache, chronic tension type, prevention

Headache, chronic tension type, prevention (off-label use):

Note: Use and dosing established with amitriptyline; nortriptyline doses are equivalent (Ref).

Oral: Initial: 10 to 25 mg once daily at bedtime; may increase dose based on response and tolerability in 10 to 25 mg increments at intervals ≥1 week, up to a maximum of 125 mg/day (Ref). May require up to 12 weeks of treatment at a therapeutic dose to adequately assess efficacy. Once effective, continue for at least 3 to 6 months before attempting gradual tapering (Ref)

Irritable bowel syndrome–associated pain and global symptoms

Irritable bowel syndrome–associated pain and global symptoms (off-label use):

Note: Due to their effect on intestinal transit, tricyclic antidepressants should be used cautiously in patients with constipation (Ref).

Oral: Initial: 10 to 25 mg once daily at bedtime; may gradually increase dose based on response and tolerability to a recommended dose of 25 to 75 mg/day (Ref). Some experts recommend 3 to 4 weeks of therapy before increasing the dose (Ref).

Major depressive disorder

Major depressive disorder (unipolar) (alternative agent): Oral: Initial: 25 to 50 mg once daily at bedtime; increase dose based on response and tolerability in 25 to 50 mg increments at intervals ≥1 week up to a usual dose of 50 to 150 mg/day (Ref). To improve tolerability, some experts suggest an initial dose of 25 mg/day at bedtime for most patients; a higher starting dose of 50 mg/day and more rapid titration (eg, every few days) may be considered in closely supervised (eg, hospitalized) settings (Ref). Maximum: 150 mg/day (Ref); however, some patients tolerate and benefit from doses up to 200 mg/day (Ref).

Migraine, prevention

Migraine, prevention (alternative agent) (off-label use):

Note: An adequate trial for assessment of effect is considered to be at least 2 to 3 months at a therapeutic dose (Ref).

Oral: Initial: 10 to 25 mg once daily at bedtime; increase dose based on response and tolerability in 10 mg increments at intervals of 1 to 2 weeks, up to 100 mg/day (Ref).

Myofascial pain syndrome and related causes of chronic pain including myofascial pelvic pain, nonradicular neck pain, temporomandibular disorders, and vulvodynia

Myofascial pain syndrome and related causes of chronic pain including myofascial pelvic pain, nonradicular neck pain, temporomandibular disorders, and vulvodynia (alternative agent) (off-label use):

Note: May consider for patients with persistent symptoms despite multimodal care and treatment with first-line agents (Ref).

Oral: Initial: 10 to 25 mg once daily at bedtime; may increase based on response and tolerability in 10 to 25 mg increments every 1 to 2 weeks to a usual dosage range of 25 to 75 mg/day (Ref). Maximum: 150 mg/day (Ref). Due to tolerability concerns, some experts avoid or use caution with doses >50 mg/day (Ref). May require 6 to 12 weeks of therapy (including 2 weeks at maximum tolerated dose) to adequately assess efficacy (Ref).

Neuropathic pain, chronic, including diabetic neuropathy

Neuropathic pain, chronic, including diabetic neuropathy (off-label use): Oral: Initial: 10 to 25 mg once daily at bedtime; may increase dose based on response and tolerability in 10 to 25 mg increments at intervals ≥1 week, up to a usual dosage range of 25 to 100 mg once daily at bedtime or in 2 divided doses. Maximum dose: 150 mg/day given once daily at bedtime or in 2 divided doses (Ref). In patients with diabetic neuropathy, some experts recommend a maximum dose of 100 mg/day (Ref). May require 6 to 12 weeks of therapy (including 2 weeks at maximum tolerated dose) to adequately assess efficacy (Ref).

Postherpetic neuralgia

Postherpetic neuralgia (alternative agent) (off-label use):

Note: May consider for patients who do not tolerate or respond to a gabapentinoid (Ref).

Oral: Initial: 10 to 20 mg once daily at bedtime; may increase daily dose based on response and tolerability in 10 to 20 mg increments at intervals of ≥3 days (typically weekly) to a maximum dose of 150 mg/day (Ref). May require 6 to 12 weeks of therapy (including 2 weeks at maximum tolerated dose) to adequately assess efficacy (Ref).

Smoking cessation

Smoking cessation (alternative agent) (off-label use):

Note: May consider, in conjunction with behavioral support, for patients who do not tolerate first-line agents or who require an adjunct to first-line therapies (Ref). Initiate ≥2 weeks before planned quit date (Ref).

Initial:

Days 1 to 3: Oral: 25 mg once daily at bedtime (Ref).

Days 4 to 7: Oral: 50 mg once daily at bedtime (Ref).

Maintenance (day 8 and later): Oral: 75 mg once daily at bedtime (Ref). Some patients may experience improved tolerability by administering in 2 or 3 divided doses. Further titration up to 125 mg/day may be needed to adequately decrease cravings in some patients (Ref).

Duration: Continue for a total of at least 12 weeks of treatment (Ref). May consider extended maintenance therapy (eg, up to 1 year) based on individualized risk-benefit assessment (Ref).

Discontinuation of therapy: When discontinuing antidepressant treatment that has lasted for ≥4 weeks, gradually taper the dose (eg, over 2 to 4 weeks) to minimize withdrawal symptoms and detect reemerging symptoms (Ref). For brief treatment (eg, 2 to 3 weeks) may taper over 1 to 2 weeks; <2 weeks treatment generally does not warrant tapering (Ref). Reasons for a slower taper (eg, over ≥4 weeks) include a history of antidepressant withdrawal symptoms or high doses of antidepressants (Ref). If intolerable withdrawal symptoms occur, resume the previously prescribed dose and/or decrease dose at a more gradual rate (Ref). Select patients (eg, those with a history of discontinuation syndrome) on long-term treatment (>6 months) may benefit from tapering over >3 months (Ref). Evidence supporting ideal taper rates is limited (Ref).

Switching antidepressants: Evidence for ideal antidepressant switching strategies is limited; strategies include cross-titration (gradually discontinuing the first antidepressant while at the same time gradually increasing the new antidepressant) and direct switch (abruptly discontinuing the first antidepressant and then starting the new antidepressant at an equivalent dose or lower dose and increasing it gradually). Cross-titration (eg, over 1 to 4 weeks depending upon sensitivity to discontinuation symptoms and adverse effects) is standard for most switches but is contraindicated when switching to or from a monoamine oxidase inhibitor (MAOI). A direct switch may be an appropriate approach when switching to another agent in the same or similar class (eg, when switching between 2 selective serotonin reuptake inhibitors), when the antidepressant to be discontinued has been used for <1 week, or when the discontinuation is for adverse effects. When choosing the switch strategy, consider the risk of discontinuation symptoms, potential for drug interactions, other antidepressant properties (eg, half-life, adverse effects, pharmacodynamics), and the degree of symptom control desired (Ref).

Switching to or from an MAOI:

Allow 14 days to elapse between discontinuing an MAOI and initiation of nortriptyline.

Allow 14 days to elapse between discontinuing nortriptyline and initiation of an MAOI.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Altered kidney function: No dosage adjustment necessary for any degree of kidney dysfunction (Ref); however, interindividual variability in clearance and half-life is high (Ref); use with caution.

Hemodialysis, intermittent (thrice weekly): Not dialyzed: No supplemental dose or dosage adjustment necessary (Ref); however, dialysis patients have demonstrated increased sensitivity to the anticholinergic effects of tricyclic antidepressants (TCAs). Use with caution along with close monitoring for both anticholinergic and QT-prolonging effects (Ref).

Peritoneal dialysis: Unlikely to be dialyzed (large Vd): No dosage adjustment necessary (expert opinion); however, dialysis patients have demonstrated increased sensitivity to the anticholinergic effects of TCAs. Use with caution along with close monitoring for both anticholinergic and QT-prolonging effects (Ref).

CRRT: Unlikely to be dialyzed: No dosage adjustment necessary (Ref).

PIRRT (eg, sustained, low-efficiency diafiltration): Unlikely to be dialyzed: No dosage adjustment necessary (Ref).

Dosing: Liver Impairment: Adult

There are no dosage adjustments provided in the manufacturer’s labeling. Nortriptyline is metabolized hepatically; use with caution. Some experts recommended reducing initial and maintenance doses by 50% in patients with hepatic impairment, with cautious dose adjustments based on response and tolerability (Ref).

Dosing: Older Adult

Note: Avoid use (Ref).

Depression: Oral: Initial: 10 to 25 mg/day given once daily or in divided doses; may increase dose based on response and tolerability in 10 to 50 mg increments at intervals of ≥1 week up to a maximum of 150 mg/day given once daily or in divided doses (Ref). Some patients tolerate and benefit from doses up to 200 mg/day (Ref).

Discontinuation of therapy: Refer to adult dosing.

Switching antidepressants: Refer to adult dosing.

Dosing: Pediatric

(For additional information see "Nortriptyline: Pediatric drug information")

Attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD): Limited data available: Note: Nortriptyline is not suggested as a therapeutic option for routine management of ADHD (Ref); however, may be considered after unsuccessful trials with other agents and comorbid conditions that may improve with nortriptyline (Ref).

Children ≥6 years and Adolescents: Oral: Initial: 0.5 mg/kg/day; may increase by 0.5 mg/kg/day increments at weekly intervals; maximum daily dose: 2 mg/kg/day up to 100 mg/day (Ref); in one trial, the daily dose was divided twice daily with a dose administered before school and a dose after dinner; reported mean effective dose: 1.8 mg/kg/day (Ref).

Major depressive disorder, unipolar

Major depressive disorder, unipolar: Note: Controlled clinical trials have not shown tricyclic antidepressants to be superior to placebo for the treatment of depression in children and adolescents. Although FDA approved in adolescents, a selective serotonin reuptake inhibitor (SSRI) is recommended first line for treatment of depression in children and adolescents with/without psychotherapeutic interventions; nortriptyline may be beneficial for patients with comorbid conditions or for those in whom first- and second-line treatment options have failed (Ref).

Adolescents: 30 to 50 mg/day in 3 to 4 divided doses or as a single daily dose; maximum daily dose: 150 mg/day.

Neuropathic pain

Neuropathic pain: Limited data available: Children and Adolescents: Oral: Initial: 0.2 mg/kg/dose at bedtime for 4 doses (days 1 to 4) then increase to 0.4 mg/kg/dose at bedtime for 4 doses (days 5 to 8); continue to titrate in 0.2 mg/kg/day increments at 4- to 5-day intervals until clinical response or intolerable side effects (constipation, dry mouth, urinary retention, sedation); maximum daily dose: 1 mg/kg/day or 50 mg/day, whichever is less (Ref). Usual effective range: 0.25 to 1 mg/kg/dose at bedtime (Ref). In some patients, may need to consider twice-daily dosing: 25% to 30% of total daily dose administered in the morning and 70% to 75% in the evening (Ref).

Discontinuation of therapy: Consider planning antidepressant therapy discontinuation for lower-stress times, recognizing non-illness-related factors could cause stress or anxiety and be misattributed to antidepressant discontinuation (Ref). Upon discontinuation of antidepressant therapy, gradually taper the dose to minimize the incidence of discontinuation syndromes (withdrawal) and allow for the detection of reemerging disease state symptoms (eg, relapse). Evidence supporting ideal taper rates after illness remission is limited. APA and NICE guidelines suggest tapering therapy over at least several weeks with consideration to the half-life of the antidepressant; antidepressants with a shorter half-life may need to be tapered more conservatively. After long-term (years) antidepressant treatment, WFSBP guidelines recommend tapering over 4 to 6 months, with close monitoring during and for 6 months after discontinuation. If intolerable discontinuation symptoms occur following a dose reduction, consider resuming the previously prescribed dose and/or decrease dose at a more gradual rate (Ref).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

Children ≥6 years and Adolescents: Oral:

Altered kidney function: There are no dosage adjustments provided in the manufacturer's labeling. Based on adult data, no dosage adjustment necessary for any degree of kidney dysfunction; however, interindividual variability in clearance and half-life is high; use with caution (Ref).

Hemodialysis: Not dialyzable.

Dosing: Liver Impairment: Pediatric

Children ≥6 years and Adolescents: Oral: There are no dosage adjustments provided in the manufacturer's labeling. Nortriptyline is metabolized hepatically; use with caution.

Adverse Reactions (Significant): Considerations
Anticholinergic effects

Nortriptyline may cause anticholinergic effects, such as constipation, xerostomia, blurred vision, palpitations, tachycardia, and urinary retention (Ref). Drugs with anticholinergic effects may increase the risk of falls in older adults (Ref).

Mechanism: Dose-related; binding affinity to the muscarinic receptor(s), permeability of the blood-brain barrier, and serum and tissue concentrations all influence the risk of anticholinergic effects (Ref).

Risk factors:

• Older age (Ref)

• Higher doses (Ref)

• Concomitant use of drugs with anticholinergic properties (Ref)

• Specific tricyclic antidepressants: Nortriptyline is considered to display modest to moderate anticholinergic activity at typical doses compared to agents with high anticholinergic effects, such as amitriptyline (Ref)

Cardiac conduction abnormalities

Tricyclic antidepressants (TCAs), including nortriptyline, are associated with cardiotoxicity, particularly at supratherapeutic doses. At therapeutic doses, TCAs can cause slowing of intraventricular conduction, manifested by prolonged PR, QRS, and QT intervals on ECG in children, adolescents, and adults (Ref). Sinus tachycardia and potentially life-threatening ventricular arrhythmias, or heart block leading to sudden cardiac death are associated with supratherapeutic doses or therapeutic doses in select patients with severe heart disease or preexisting conduction disorders (eg, Brugada syndrome or bundle branch block, long QT syndrome) (Ref).

Mechanism: Dose-related (some mechanisms); at therapeutic doses, TCAs inhibit sodium channel conduction, potentially delaying cardiac depolarization and causing prolongation of the QRS complex on ECG. Multiple other mechanisms contribute to the cardiac effects associated with TCAs, including inhibition of central cholinergic neurotransmission (potentially causing tachycardia), norepinephrine reuptake inhibition (potentially exacerbating tachycardia), and blockade of alpha-adrenergic receptors (potentially lowering systemic vascular resistance and causing hypotension or orthostatic hypotension). In addition, high doses increase sympathetic and decrease parasympathetic effects on heart rate (Ref). Sinus tachycardia is attributed to the inhibition of norepinephrine and nortriptyline's anticholinergic action (Ref).

Risk factors:

• Increased age (Ref)

• Females (Ref)

• Hypokalemia (Ref)

• Coronary artery disease (Ref)

• Coadministration of drugs independently associated with QT interval prolongation or further increase risk of arrhythmia (nortriptyline shares electrophysiologic properties of type IA antiarrhythmics such as quinidine, procainamide, and disopyramide) (Ref)

• Preexisting conduction disease, particularly bundle branch block or Brugada syndrome, or family history of congenital long QT syndrome (Ref). Note: Use is relatively contraindicated in patients with conduction abnormalities.

• Higher doses, particularly in children (Ref)

CNS depression

Tricyclic antidepressants (TCAs), including nortriptyline, may cause dose-dependent CNS depression, including dizziness, drowsiness, ataxia, cognitive dysfunction (particularly in older adults), confusion, disorientation, fatigue, and psychomotor impairment (Ref).

Mechanism: Dose-related; drowsiness and psychomotor effects are due to anticholinergic and antihistaminergic properties of TCAs, with varying degrees of effects depending on the specific agent. TCAs also produce alpha-adrenergic blockade which can contribute to sedation and dizziness (from orthostatic hypotension) (Ref).

Onset: Varied; difficult to define; some symptoms may occur with first dose.

Risk factors (TCAs in general):

• Concomitant alcohol

• Concomitant CNS depressants (eg, anticholinergics, antihistamines) (Ref)

• Females (Ref)

• Older adults (Ref)

• Increased TCA plasma levels (Ref)

• Specific TCA: Nortriptyline is associated with a low propensity for causing sedation relative to TCAs associated with high levels of sedation, such as amitriptyline (Ref). Nortriptyline is associated with a modest to moderate propensity for producing anticholinergic effects (Ref)

Fractures

Antidepressants have been associated with an increased risk of falls and bone fractures in observational studies (Ref). Tricyclic antidepressants (TCAs) have also been associated with an increased fracture risk; however, risk varies by agent and the evidence is conflicting, particularly with nortriptyline (Ref).

Mechanism: Not fully elucidated; per selective serotonin reuptake inhibitor-derived literature, may be related to a direct effect on bone metabolism via interaction with 5-HT and osteoblast, osteocyte, and/or osteoclast activity (Ref). Of note, nortriptyline is associated with low 5-HT (serotonin) transporter inhibition compared to its effect on norepinephrine inhibition (Ref). Fall risk with TCAs may also be attributed to sedation, syncope, orthostatic hypotension, and/or confusion (Ref).

Onset: Intermediate; observational studies suggest the increased fracture risk observed with TCAs occurs early and reaches a peak within 1 month of initiation of therapy (Ref)

Risk factors (TCAs in general):

• Concomitant use with other agents that may further affect physical balance and contribute to falls (eg, anxiolytics) (Ref)

Hyponatremia

Tricyclic antidepressants (TCAs), including nortriptyline, have been rarely associated with syndrome of inappropriate antidiuretic hormone secretion (SIADH) and/or hyponatremia, predominately in the elderly (Ref).

Mechanism: May cause SIADH via release of antidiuretic hormone (ADH) (Ref) or may cause nephrogenic SIADH by increasing the sensitivity of the kidney to ADH (Ref).

Onset: Varied; overall, hyponatremia risk is much higher within 2 to 4 weeks of initiating antidepressant therapy and the risk seems to diminish over time. By 3 to 6 months, the hyponatremia risk is the same as for patients who do not take antidepressants (Ref).

Risk factors:

Older age (Ref)

• Females (Ref)

Concomitant use of diuretics (Ref)

Low body weight (Ref)

Severe physical illness (Ref)

Lower baseline serum sodium concentration (selective serotonin reuptake inhibitor [SSRI]–derived literature) (Ref)

Volume depletion (potential risk factor; SSRI-derived literature) (Ref)

History of hyponatremia (potential risk factor) (Ref)

Symptoms of psychosis (potential risk factor) (Ref)

Specific antidepressant: TCAs have a lower risk for hyponatremia in comparison to SSRIs (Ref)

Ocular effects

Tricyclic antidepressants (TCAs) may cause mydriasis (pupillary dilation) and cycloplegia (affected eyes cannot focus on nearby objects), resulting in transient accommodation disturbances and blurred vision (Ref). Mydriasis and cycloplegia usually improve over time as patients develop a tolerance to these effects (Ref). In susceptible individuals, TCA-induced mydriasis may result in the exacerbation of chronic angle-closure glaucoma and/or induction of acute angle-closure glaucoma (AACG). AACG may cause symptoms including eye pain, changes in vision, swelling, and redness, which can rapidly lead to permanent blindness if not treated (Ref).

Mechanism: Mydriasis and cycloplegia are likely due to the anticholinergic effect of TCAs (Ref). TCA-induced effects on norepinephrine and serotonin receptors in the iris and ciliary body of the eye, as well as alpha-adrenergic receptors may also play a role (Ref). In susceptible individuals, mydriasis can lead to AACG, which is caused by the physical obstruction of the outflow of intraocular fluid.

Onset: Blurred vision occurs in the initial stages of treatment with a TCA (Ref).

Risk factors:

For AACG:

• Females (Ref)

≥50 years of age (slight increase) (Ref)

Hyperopia (slight increase) (Ref)

Personal or family history of AACG (Ref)

Inuit or Asian descent (Ref)

Narrow-angle glaucoma (avoid or use with extreme caution in these patients) (Ref)

Specific tricyclic antidepressants: Nortriptyline is considered to display modest to moderate anticholinergic activity at typical doses (Ref)

Orthostatic hypotension

Tricyclic antidepressants (TCAs), including nortriptyline, may cause orthostatic hypotension, which may lead to syncope and subsequent falls, particularly in older adults (Ref).

Mechanism: Alpha-adrenergic receptor blockade may lower systemic vascular resistance and result in hypotension, including orthostatic hypotension (Ref).

Onset: In a small study of older adults ≥55 years of age treated with nortriptyline (mean dose: 79 mg/day), orthostatic hypotension appeared during the first week and generally persisted throughout the 7-week study period (Ref).

Risk factors:

Cardiovascular disease

Hypovolemia/dehydration (Ref)

Concurrent medication use that may predispose to hypotension/bradycardia (Ref)

Older adults, especially in those with preexisting heart conditions (Ref)

Specific TCA: Nortriptyline is associated with a lower risk of significant orthostatic hypotension compared to other TCAs (Ref)

Serotonin syndrome

Serotonin syndrome has been reported and typically occurs with coadministration of multiple drugs with serotonin activity (Ref). The diagnosis of serotonin syndrome is made based on the Hunter Serotonin Toxicity Criteria (Ref) and may result in a spectrum of symptoms, such as anxiety, agitation, confusion, delirium, hyperreflexia, muscle rigidity, myoclonus, tachycardia, tachypnea, hypertension, mydriasis, diaphoresis, and tremor. Severe cases may cause hyperthermia, significant autonomic instability (ie, rapid and severe changes in blood pressure and pulse), coma, and seizures (Ref).

Mechanism: Dose-related; overstimulation of serotonin receptors by serotonergic agents (Ref).

Onset: Rapid; in the majority of cases (74%), onset occurred within 24 hours of treatment initiation, overdose, or change in dose (Ref).

Risk factors:

• Concomitant use of drugs that increase serotonin synthesis, block serotonin reuptake, and/or impair serotonin metabolism (eg, monoamine oxidase inhibitors [MAOIs]). Of note, concomitant use of some serotonergic agents, such as MAOIs, is contraindicated.

Suicidal thinking and behavior

Antidepressants have been associated with an increased risk of suicidal thinking and suicidal behavior in pediatric and young adult patients (18 to 24 years) in short-term studies, per product labeling. In adults >24 years of age, short-term studies did not show an increased risk of suicidal thinking and behavior, and in older adults ≥65 years of age, a decreased risk was observed. Although data have yielded inconsistent results regarding the association of antidepressants and risk of suicide, particularly among adults, some evidence shows a trend of an elevated risk of suicidality in younger age groups with certain antidepressants (Ref). Additionally, an observational study suggested an association with decreased rate of antidepressant prescribing and an increase in suicide rates in children and adolescents after the labeling was updated with the warnings (Ref). Of note, the risk of a suicide attempt is inherent in major depression and may persist until remission occurs.

Mechanism: Not established; one of several postulated mechanisms is antidepressants may energize suicidal patients to act on impulses (Ref).

Onset: Varied; increased risk observed in short-term studies (ie, <4 months) in pediatric and young adults; it is unknown whether this risk extends to long-term use (ie, >4 months).

Risk factors:

Children and adolescents (Ref)

Depression (risk of suicide is associated with major depression and may persist until remission occurs)

Withdrawal syndrome

Withdrawal syndrome has been reported in children and adults, primarily following abrupt discontinuation of tricyclic antidepressants (TCAs). Common symptoms include somatic symptoms (eg, lethargy, headache, tremor, sweating, anorexia); affective symptoms (eg, irritability, anxiety, agitation, low mood); sleep disorders (insomnia, excessive dreaming); and gastrointestinal disturbances (eg, nausea/vomiting, abdominal pain, anorexia). Rarely, movement disorders, such as akathisia or parkinsonism, hypomania/mania, psychosis, and/or cardiac arrhythmias may also occur. Of note, sensory abnormalities (eg, shock-like sensations, numbness), which are commonly reported with selective serotonin reuptake inhibitor withdrawal, are rarely seen with TCA withdrawal. Withdrawal symptoms may also occur following gradual tapering (Ref).

Mechanism: Withdrawal; due to reduced availability of serotonin in the CNS with decreasing levels of the serotonergic agent. Other neurotransmission systems, including increased glutamine and dopamine, may also be affected, as well as the hypothalamic-pituitary-adrenal axis (Ref). TCA-associated withdrawal symptoms may also be related in part to an adaptive hypersensitivity of muscarinic cholinergic receptors called cholinergic rebound or cholinergic overdrive and to involve noradrenergic mechanisms (Ref).

Onset: Symptoms generally appear within a few days of stopping or reducing the dosage of the antidepressant. Onset >1 week later is unusual (Ref).

Risk factors:

Abrupt discontinuation (rather than dose taper) or tapering the antidepressant too quickly (Ref)

Drugs with a half-life <24 hours (eg, paroxetine, venlafaxine) (Ref)

• Higher doses (Ref)

• Longer duration of treatment (eg, ≥4 weeks) (Ref)

Prior history of antidepressant withdrawal symptoms (Ref)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Some reactions listed are based on reports for other agents in this same pharmacologic class and may not be specifically reported for nortriptyline.

<1%: Gastrointestinal: Sublingual adenitis

Frequency not defined:

Cardiovascular: Acute myocardial infarction, cardiac arrhythmia (Ref), cerebrovascular accident, edema, flushing, heart block, hypertension, hypotension, orthostatic hypotension (Ref), palpitations, tachycardia

Dermatologic: Alopecia, diaphoresis (excessive), pruritus, skin photosensitivity, skin rash, urticaria

Endocrine & metabolic: Decreased libido, galactorrhea not associated with childbirth, gynecomastia, increased libido, increased serum glucose, SIADH, weight gain, weight loss

Gastrointestinal: Abdominal cramps, anorexia, constipation, diarrhea, epigastric discomfort, melanoglossia, nausea, paralytic ileus, parotid gland enlargement, stomatitis, unpleasant taste, vomiting, xerostomia

Genitourinary: Breast hypertrophy, impotence, nocturia, testicular swelling, urinary frequency, urinary hesitancy, urinary retention, urinary tract dilation

Hematologic & oncologic: Agranulocytosis, bone marrow depression, eosinophilia, petechia, purpuric disease, thrombocytopenia

Hepatic: Abnormal liver function, cholestatic jaundice

Hypersensitivity: Drug-induced hypersensitivity reaction (tricyclic class)

Nervous system: Agitation, anxiety, ataxia, confusion, delusion, disorientation, dizziness, drowsiness, drug fever, EEG pattern changes, exacerbation of depression, extrapyramidal reaction, fatigue, hallucination, headache, hypomania, insomnia, nightmares, numbness, panic, peripheral neuropathy, restlessness, seizure, tingling of extremities, tingling sensation, withdrawal syndrome (Ref)

Neuromuscular & skeletal: Asthenia, tremor

Ophthalmic: Accommodation disturbance, blurred vision, mydriasis

Otic: Tinnitus

Renal: Polyuria

Postmarketing:

Cardiovascular: Cardiac conduction disorder (Brugada syndrome exacerbation) (Ref), prolonged QT interval on ECG (Ref), sinus tachycardia (Ref), widened QRS complex on ECG (Ref)

Dermatologic: Pityriasis rosea (pityriasis rosea-like drug eruption) (Ref)

Nervous system: Cognitive dysfunction (Ref), psychomotor impairment (Ref), psychosis (including exacerbation of and associated with withdrawal syndrome) (Ref), serotonin syndrome (Ref), suicidal ideation, suicidal tendencies

Ophthalmic: Angle-closure glaucoma

Contraindications

Hypersensitivity to nortriptyline and similar chemical class dibenzazepines, or any component of the formulation; use in a patient during the acute recovery phase of myocardial infarction; use of monoamine oxidase inhibitors (MAOIs) (concurrently or within 14 days of discontinuing either nortriptyline or the MAOI); initiation of nortriptyline in a patient receiving IV methylene blue.

Note: Although nortriptyline is contraindicated per the manufacturer labeling when used in combination with linezolid, new evidence suggests that the combination is unlikely to cause serotonin syndrome (0.06% to 3% risk), and therefore these agents can be administered concomitantly when necessary. Monitor patients on this combination; average duration of serotonin toxicity is ~4 days; however, risks may be greater with longer durations of concurrent therapy. Educate patients on the signs and symptoms of serotonin syndrome (Bai 2022; Butterfield 2012; Karkow 2017; Kufel 2023; Narita 2007; Taylor 2006).

Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Warnings/Precautions

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with a history of cardiovascular disease (including previous MI, stroke, tachycardia).

• Diabetes: Use with caution in patients with diabetes mellitus; a causal relationship of tricyclic antidepressants with poor glycemic control has not been established, although some evidence of association exists. In addition, depression may reduce adherence to diabetic therapies (APA 2010).

• GI motility: Use with caution in patients with decreased GI motility (eg, paralytic ileus) as anticholinergic effects may exacerbate underlying condition.

• Hepatic impairment: Use with caution in patients with hepatic impairment; clearance of TCAs is decreased. Due to the narrow therapeutic index, use lower initial and maintenance doses of TCAs. Use caution in patients with hepatic encephalopathy due to the risk of neurocognitive effects (Mullish 2014).

• Mania/hypomania: May precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Combination therapy with an antidepressant and a mood stabilizer should also be avoided in acute mania or mixed episodes, as well as maintenance treatment in bipolar disorder due to the mood-destabilizing effects of antidepressants (CANMAT [Yatham 2018]; WFSBP [Grunze 2018]). Patients presenting with depressive symptoms should be screened for bipolar disorder. Nortriptyline is not FDA approved for the treatment of bipolar depression.

• Ophthalmic conditions: Use with caution in patients with certain ophthalmic conditions as anticholinergic effects may exacerbate underlying condition.

• Renal impairment: Use with caution in patients with renal impairment.

• Seizure disorder: Use with caution in patients with a history of seizures.

• Urinary retention (eg, benign prostatic hyperplasia): Use with caution in patients with urinary retention as anticholinergic effects may exacerbate underlying condition.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.

Other warnings/precautions:

• Surgery: Recommended by the manufacturer to discontinue prior to elective surgery; risks exist for drug interactions with anesthesia and for cardiac arrhythmias. However, some experts recommend continuing tricyclic antidepressants prior to surgery (Pass 2004). Therapy should not be abruptly discontinued in patients receiving high doses for prolonged periods.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Pamelor: 10 mg, 25 mg [contains fd&c yellow #6 (sunset yellow), quinoline yellow (d&c yellow #10)]

Pamelor: 50 mg

Pamelor: 75 mg [contains fd&c yellow #6 (sunset yellow), quinoline yellow (d&c yellow #10)]

Generic: 10 mg, 25 mg, 50 mg, 75 mg

Solution, Oral:

Generic: 10 mg/5 mL (473 mL)

Generic Equivalent Available: US

Yes

Pricing: US

Capsules (Nortriptyline HCl Oral)

10 mg (per each): $0.73 - $0.74

25 mg (per each): $1.47

50 mg (per each): $2.77

75 mg (per each): $4.22

Capsules (Pamelor Oral)

10 mg (per each): $47.15

25 mg (per each): $48.10

50 mg (per each): $49.04

75 mg (per each): $49.98

Solution (Nortriptyline HCl Oral)

10 mg/5 mL (per mL): $0.48

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral:

Aventyl: 10 mg, 25 mg

Generic: 10 mg [DSC], 25 mg [DSC]

Administration: Pediatric

Oral: Capsule, oral solution: May administer without regard to food; in pediatric patients, the timing of doses dependent upon use; for neuropathic pain, doses administered at bedtime if once daily; if divided twice daily, the larger daily dose should be administered at bedtime (Ref).

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/ucm088671.pdf, must be dispensed with this medication.

Use: Labeled Indications

Major depressive disorder, unipolar: Treatment of symptoms of unipolar major depressive disorder.

Use: Off-Label: Adult

Cyclic vomiting syndrome, moderate to severe, prevention; Functional dyspepsia; Headache, chronic tension-type, prevention; Irritable bowel syndrome–associated pain and global symptoms; Migraine, prevention; Myofascial pain syndrome and related causes of chronic pain including myofascial pelvic pain, nonradicular neck pain, temporomandibular disorders, and vulvodynia; Neuropathic pain, chronic, including diabetic neuropathy; Postherpetic neuralgia; Smoking cessation

Medication Safety Issues
Sound-alike/look-alike issues:

Aventyl HCl may be confused with Bentyl

Nortriptyline may be confused with amitriptyline, desipramine, Norpramin

Pamelor may be confused with Demerol, Tambocor [DSC]

Older Adult: High-Risk Medication:

Beers Criteria: Nortriptyline is identified in the Beers Criteria as a potentially inappropriate medication to be avoided in patients 65 years and older (independent of diagnosis or condition) due to its strong anticholinergic properties and potential for sedation and orthostatic hypotension. In addition, use TCAs with caution due to their potential to cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia; monitor sodium closely with initiation or dosage adjustments in older adults (Beers Criteria [AGS 2023]).

Metabolism/Transport Effects

Substrate of CYP1A2 (Minor), CYP2C19 (Minor), CYP2D6 (Major), CYP3A4 (Minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential;

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.

Acetylcholinesterase Inhibitors: May decrease therapeutic effects of Agents with Clinically Relevant Anticholinergic Effects. Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Acetylcholinesterase Inhibitors. Risk C: Monitor

Aclidinium: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid

Acrivastine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

Acrivastine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Agents with Clinically Relevant Anticholinergic Effects: May increase anticholinergic effects of Tricyclic Antidepressants. Risk C: Monitor

Ajmaline: May increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor

Alcohol (Ethyl): CNS Depressants may increase CNS depressant effects of Alcohol (Ethyl). Risk C: Monitor

Alizapride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Almotriptan: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Alosetron: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Alpha-/Beta-Agonists: Tricyclic Antidepressants may increase vasopressor effects of Alpha-/Beta-Agonists. Management: Avoid, if possible, the use of alpha-/beta-agonists in patients receiving tricyclic antidepressants. If combined, monitor for evidence of increased pressor effects and consider reductions in initial dosages of the alpha-/beta-agonist. Risk D: Consider Therapy Modification

Alpha1-Agonists: Tricyclic Antidepressants may increase therapeutic effects of Alpha1-Agonists. Tricyclic Antidepressants may decrease therapeutic effects of Alpha1-Agonists. Risk C: Monitor

Alpha2-Agonists (Ophthalmic): Tricyclic Antidepressants may decrease therapeutic effects of Alpha2-Agonists (Ophthalmic). Risk C: Monitor

Alpha2-Agonists: Tricyclic Antidepressants may decrease antihypertensive effects of Alpha2-Agonists. Management: Consider avoiding this combination. If used, monitor for decreased effects of the alpha2-agonist. Exercise great caution if discontinuing an alpha2-agonist in a patient receiving a TCA. Risk D: Consider Therapy Modification

Amantadine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

Amifampridine: Agents With Seizure Threshold Lowering Potential may increase neuroexcitatory and/or seizure-potentiating effects of Amifampridine. Risk C: Monitor

Amisulpride (Oral): Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Amisulpride (Oral). Specifically, the risk of seizures may be increased. Risk C: Monitor

Amisulpride (Oral): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Amphetamines: Tricyclic Antidepressants may increase adverse/toxic effects of Amphetamines. Tricyclic Antidepressants may potentiate the cardiovascular effects of Amphetamines. Amphetamines may increase serotonergic effects of Tricyclic Antidepressants. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and increased cardiovascular effects when these agents are combined. Risk C: Monitor

Antiemetics (5HT3 Antagonists): May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

ARIPiprazole Lauroxil: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of ARIPiprazole Lauroxil. Specifically, the risk of seizures may be increased. Risk C: Monitor

ARIPiprazole: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of ARIPiprazole. Specifically, the risk of seizures may be increased. Risk C: Monitor

Artemether and Lumefantrine: May increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor

Articaine: May increase CNS depressant effects of CNS Depressants. Management: Consider reducing the dose of articaine if possible when used in patients who are also receiving CNS depressants. Monitor for excessive CNS depressant effects with any combined use. Risk D: Consider Therapy Modification

Asenapine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Asenapine. Specifically, the risk of seizures may be increased. Risk C: Monitor

Azelastine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid

Baclofen: Tricyclic Antidepressants may increase adverse neuromuscular effects of Baclofen. Baclofen may increase CNS depressant effects of Tricyclic Antidepressants. Risk C: Monitor

Barbiturates: May increase metabolism of Tricyclic Antidepressants. Management: Monitor for decreased efficacy of tricyclic antidepressants if a barbiturate is initiated/dose increased, or increased effects if a barbiturate is discontinued/dose decreased. Tricyclic antidepressant dose adjustments are likely required. Risk D: Consider Therapy Modification

Benperidol: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Benperidol. Risk C: Monitor

Benperidol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Benperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor

Benperidol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Benztropine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Benztropine. Risk C: Monitor

Beta-Acetyldigoxin: Tricyclic Antidepressants may increase arrhythmogenic effects of Beta-Acetyldigoxin. Risk C: Monitor

Beta2-Agonists: Tricyclic Antidepressants may increase adverse/toxic effects of Beta2-Agonists. Risk C: Monitor

Biperiden: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Biperiden. Risk C: Monitor

Blonanserin: CNS Depressants may increase CNS depressant effects of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider Therapy Modification

Bornaprine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Bornaprine. Risk C: Monitor

Botulinum Toxin-Containing Products: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

Brexanolone: CNS Depressants may increase CNS depressant effects of Brexanolone. Risk C: Monitor

Brexpiprazole: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Brexpiprazole. Specifically, the risk of seizures may be increased. Risk C: Monitor

Brimonidine (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Bromopride: May increase adverse/toxic effects of Tricyclic Antidepressants. Risk X: Avoid

Bromperidol: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid

Buclizine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Buclizine. Risk C: Monitor

Buclizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Buprenorphine: CNS Depressants may increase CNS depressant effects of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider Therapy Modification

BuPROPion: Tricyclic Antidepressants may increase neuroexcitatory and/or seizure-potentiating effects of BuPROPion. BuPROPion may increase serum concentration of Tricyclic Antidepressants. Risk C: Monitor

BusPIRone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

BusPIRone: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Cannabinoid-Containing Products: Agents with Clinically Relevant Anticholinergic Effects may increase tachycardic effects of Cannabinoid-Containing Products. Risk C: Monitor

Cannabinoid-Containing Products: CNS Depressants may increase CNS depressant effects of Cannabinoid-Containing Products. Risk C: Monitor

CarBAMazepine: May decrease serum concentration of Tricyclic Antidepressants. Risk C: Monitor

Cariprazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Cariprazine. Specifically, the risk of seizures may be increased. Risk C: Monitor

Cetirizine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk D: Consider Therapy Modification

Chloral Hydrate/Chloral Betaine: CNS Depressants may increase CNS depressant effects of Chloral Hydrate/Chloral Betaine. Management: Consider alternatives to the use of chloral hydrate or chloral betaine and additional CNS depressants. If combined, consider a dose reduction of either agent and monitor closely for enhanced CNS depressive effects. Risk D: Consider Therapy Modification

Chlormethiazole: May increase CNS depressant effects of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider Therapy Modification

Chlorphenesin Carbamate: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor

ChlorproMAZINE: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of ChlorproMAZINE. Specifically, the risk of seizures may be increased. Risk C: Monitor

Chlorprothixene: May increase QTc-prolonging effects of Tricyclic Antidepressants. Risk X: Avoid

Cimetidine: May increase serum concentration of Tricyclic Antidepressants. Risk C: Monitor

Cimetropium: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Cimetropium. Risk X: Avoid

Citalopram: Tricyclic Antidepressants may increase serotonergic effects of Citalopram. Tricyclic Antidepressants may increase serum concentration of Citalopram. Citalopram may increase serum concentration of Tricyclic Antidepressants. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and increased TCA and citalopram concentrations/effects. Risk C: Monitor

Clothiapine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Clothiapine. Specifically, the risk of seizures may be increased. Risk C: Monitor

CloZAPine: Agents with Clinically Relevant Anticholinergic Effects may increase constipating effects of CloZAPine. Management: Consider alternatives to this combination whenever possible. If combined, monitor closely for signs and symptoms of gastrointestinal hypomotility and consider prophylactic laxative treatment. Risk D: Consider Therapy Modification

CNS Depressants: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor

Cocaine (Topical): May increase adverse/toxic effects of Tricyclic Antidepressants. Risk C: Monitor

Cyclizine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

Cyclobenzaprine: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

CYP2D6 Inhibitors (Moderate): May increase serum concentration of Nortriptyline. Risk C: Monitor

CYP2D6 Inhibitors (Strong): May increase serum concentration of Nortriptyline. Risk C: Monitor

Dantrolene: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Dapoxetine: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Do not use serotonergic agents (high risk) with dapoxetine or within 7 days of serotonergic agent discontinuation. Do not use dapoxetine within 14 days of monoamine oxidase inhibitor use. Dapoxetine labeling lists this combination as contraindicated. Risk X: Avoid

Daridorexant: May increase CNS depressant effects of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider Therapy Modification

Darifenacin: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Darifenacin. Risk C: Monitor

Desmopressin: Tricyclic Antidepressants may increase hyponatremic effects of Desmopressin. Risk C: Monitor

DexmedeTOMIDine: CNS Depressants may increase CNS depressant effects of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider Therapy Modification

Dexmethylphenidate-Methylphenidate: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Dextromethorphan: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Dicyclomine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Dicyclomine. Risk C: Monitor

Difelikefalin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Difenoxin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Dihydralazine: CNS Depressants may increase hypotensive effects of Dihydralazine. Risk C: Monitor

Dimethindene (Systemic): Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Dimethindene (Systemic). Risk C: Monitor

Dimethindene (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Dothiepin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Doxylamine: CNS Depressants may increase CNS depressant effects of Doxylamine. Risk C: Monitor

DroNABinol: Agents with Clinically Relevant Anticholinergic Effects may increase tachycardic effects of DroNABinol. Risk X: Avoid

Dronedarone: Tricyclic Antidepressants may increase arrhythmogenic effects of Dronedarone. Risk X: Avoid

DroPERidol: May increase CNS depressant effects of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider Therapy Modification

DULoxetine: May increase serotonergic effects of Tricyclic Antidepressants. This could result in serotonin syndrome. DULoxetine may increase serum concentration of Tricyclic Antidepressants. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and increased TCA concentrations and effects if these agents are combined. Risk C: Monitor

Eletriptan: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Eluxadoline: Agents with Clinically Relevant Anticholinergic Effects may increase constipating effects of Eluxadoline. Risk X: Avoid

Emedastine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk C: Monitor

Entacapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Epinephrine (Racemic): Tricyclic Antidepressants may increase adverse/toxic effects of Epinephrine (Racemic). Risk X: Avoid

Ergot Derivatives: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Escitalopram: Tricyclic Antidepressants may increase serotonergic effects of Escitalopram. Escitalopram may increase serum concentration of Tricyclic Antidepressants. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and increased TCA concentrations/effects if these agents are combined. Risk C: Monitor

Esketamine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Fenfluramine: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor

Fesoterodine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Fesoterodine. Risk C: Monitor

Flunarizine: CNS Depressants may increase CNS depressant effects of Flunarizine. Risk X: Avoid

Flunitrazepam: CNS Depressants may increase CNS depressant effects of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider Therapy Modification

FLUoxetine: May increase serotonergic effects of Tricyclic Antidepressants. FLUoxetine may increase serum concentration of Tricyclic Antidepressants. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and increased TCA concentrations/effects if these agents are combined. Risk D: Consider Therapy Modification

Flupentixol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Flupentixol. Specifically, the risk of seizures may be increased. Risk C: Monitor

FluPHENAZine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of FluPHENAZine. Specifically, the risk of seizures may be increased. Risk C: Monitor

FluPHENAZine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

FluvoxaMINE: May increase serotonergic effects of Tricyclic Antidepressants. FluvoxaMINE may increase serum concentration of Tricyclic Antidepressants. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and increased TCA concentrations/effects if these agents are combined. Risk C: Monitor

Gastrointestinal Agents (Prokinetic): Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Gastrointestinal Agents (Prokinetic). Risk C: Monitor

Gepirone: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor

Gepotidacin: May decrease anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

Glucagon: Agents with Clinically Relevant Anticholinergic Effects may increase adverse/toxic effects of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Risk C: Monitor

Glycopyrrolate (Oral Inhalation): Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Glycopyrrolate (Oral Inhalation). Risk X: Avoid

Glycopyrrolate (Systemic): Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Glycopyrrolate (Systemic). Risk C: Monitor

Glycopyrronium (Topical): May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid

Guanethidine: Tricyclic Antidepressants may decrease therapeutic effects of Guanethidine. Risk C: Monitor

Haloperidol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Haloperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor

Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may increase QTc-prolonging effects of Haloperidol. Risk C: Monitor

HydrOXYzine: May increase CNS depressant effects of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider Therapy Modification

Iloperidone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Iloperidone. Specifically, the risk of seizures may be increased. Risk C: Monitor

Iobenguane Radiopharmaceutical Products: Tricyclic Antidepressants may decrease therapeutic effects of Iobenguane Radiopharmaceutical Products. Management: Discontinue all drugs that may inhibit or interfere with catecholamine transport or uptake for at least 5 biological half-lives before iobenguane administration. Do not administer these drugs until at least 7 days after each iobenguane dose. Risk X: Avoid

Iohexol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider Therapy Modification

Iomeprol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider Therapy Modification

Iopamidol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider Therapy Modification

Ipratropium (Nasal): May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

Ipratropium (Oral Inhalation): May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid

Itopride: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Itopride. Risk C: Monitor

Ixabepilone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Kava Kava: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Ketotifen (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Kratom: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid

Lasmiditan: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Lemborexant: May increase CNS depressant effects of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider Therapy Modification

Levocetirizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Levosulpiride: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Levosulpiride. Risk X: Avoid

Linezolid: May increase serotonergic effects of Tricyclic Antidepressants. This could result in serotonin syndrome. Risk X: Avoid

Lisuride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Lofepramine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Lofexidine: Tricyclic Antidepressants may decrease therapeutic effects of Lofexidine. Management: Consider avoiding this drug combination when possible. If concurrent administration is required, monitor blood pressure carefully at the beginning of the combined therapy and when either drug is stopped. Adjust the dosage accordingly. Risk D: Consider Therapy Modification

Loxapine: CNS Depressants may increase CNS depressant effects of Loxapine. Management: Consider reducing the dose of CNS depressants administered concomitantly with loxapine due to an increased risk of respiratory depression, sedation, hypotension, and syncope. Risk D: Consider Therapy Modification

Lumateperone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Lumateperone. Specifically, the risk of seizures may be increased. Risk C: Monitor

Lurasidone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Lurasidone. Specifically, the risk of seizures may be increased. Risk C: Monitor

Magnesium Sulfate: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Maprotiline: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Maprotiline. Risk C: Monitor

Mavorixafor: May increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk X: Avoid

Melitracen [INT]: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Melperone: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

Melperone: Tricyclic Antidepressants may increase adverse/toxic effects of Melperone. Melperone may increase adverse/toxic effects of Tricyclic Antidepressants. Melperone may increase serum concentration of Tricyclic Antidepressants. Risk C: Monitor

Mequitazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Metaxalone: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Metergoline: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Methotrimeprazine: CNS Depressants may increase CNS depressant effects of Methotrimeprazine. Methotrimeprazine may increase CNS depressant effects of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider Therapy Modification

Methoxyflurane: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Methscopolamine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Methscopolamine. Risk C: Monitor

Methylene Blue: Tricyclic Antidepressants may increase serotonergic effects of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid

Metoclopramide: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Metoclopramide: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Consider monitoring for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

MetyroSINE: CNS Depressants may increase sedative effects of MetyroSINE. Risk C: Monitor

Minocycline (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Mirabegron: Agents with Clinically Relevant Anticholinergic Effects may increase adverse/toxic effects of Mirabegron. Risk C: Monitor

Molindone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Molindone. Specifically, the risk of seizures may be increased. Risk C: Monitor

Monoamine Oxidase Inhibitors (Antidepressant): May increase serotonergic effects of Tricyclic Antidepressants. This could result in serotonin syndrome. Risk X: Avoid

Nabilone: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid

Nalfurafine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Nefazodone: Tricyclic Antidepressants may increase serotonergic effects of Nefazodone. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Nicorandil: Tricyclic Antidepressants may increase hypotensive effects of Nicorandil. Risk C: Monitor

Nitroglycerin: Agents with Clinically Relevant Anticholinergic Effects may decrease absorption of Nitroglycerin. Specifically, anticholinergic agents may decrease the dissolution of sublingual nitroglycerin tablets, possibly impairing or slowing nitroglycerin absorption. Risk C: Monitor

Nonsteroidal Anti-Inflammatory Agents: Tricyclic Antidepressants may increase antiplatelet effects of Nonsteroidal Anti-Inflammatory Agents. Tricyclic Antidepressants may increase adverse/toxic effects of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk of major adverse cardiac events (MACE), hemorrhagic stroke, ischemic stroke, and heart failure may be increased. Risk C: Monitor

Noscapine: CNS Depressants may increase adverse/toxic effects of Noscapine. Risk X: Avoid

OLANZapine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of OLANZapine. Risk C: Monitor

OLANZapine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of OLANZapine. Specifically, the risk of seizures may be increased. Risk C: Monitor

Olopatadine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid

Ondansetron: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Opicapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Opioid Agonists: CNS Depressants may increase CNS depressant effects of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider Therapy Modification

Opipramol: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

Opipramol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Opipramol: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Orphenadrine: CNS Depressants may increase CNS depressant effects of Orphenadrine. Risk X: Avoid

Oxatomide: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid

Oxitriptan: Serotonergic Agents (High Risk) may increase serotonergic effects of Oxitriptan. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Oxomemazine: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid

Oxybate Salt Products: CNS Depressants may increase CNS depressant effects of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider Therapy Modification

OxyBUTYnin: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of OxyBUTYnin. Risk C: Monitor

OxyCODONE: CNS Depressants may increase CNS depressant effects of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider Therapy Modification

Paliperidone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Paliperidone. Specifically, the risk of seizures may be increased. Risk C: Monitor

Paliperidone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Paraldehyde: CNS Depressants may increase CNS depressant effects of Paraldehyde. Risk X: Avoid

PARoxetine: May increase serotonergic effects of Tricyclic Antidepressants. PARoxetine may increase serum concentration of Tricyclic Antidepressants. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and increased TCA concentrations/effects if these agents are combined. Risk D: Consider Therapy Modification

Peginterferon Alfa-2b: May decrease serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor

Perampanel: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Perazine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

Periciazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Periciazine. Specifically, the risk of seizures may be increased. Risk C: Monitor

Periciazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Perphenazine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Perphenazine. Risk C: Monitor

Perphenazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Perphenazine. Specifically, the risk of seizures may be increased. Risk C: Monitor

Pimozide: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Pimozide. Specifically, the risk of seizures may be increased. Risk C: Monitor

Pipamperone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Pipamperone. Specifically, the risk of seizures may be increased. Risk X: Avoid

Piribedil: CNS Depressants may increase CNS depressant effects of Piribedil. Risk C: Monitor

Pitolisant: Tricyclic Antidepressants may decrease therapeutic effects of Pitolisant. Risk X: Avoid

Pizotifen: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Polyethylene Glycol-Electrolyte Solution: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Polyethylene Glycol-Electrolyte Solution. Specifically, the risk of seizure may be increased. Risk C: Monitor

Potassium Chloride: Agents with Clinically Relevant Anticholinergic Effects may increase ulcerogenic effects of Potassium Chloride. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium chloride. Risk X: Avoid

Potassium Citrate: Agents with Clinically Relevant Anticholinergic Effects may increase ulcerogenic effects of Potassium Citrate. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium citrate. Risk X: Avoid

Pramipexole: CNS Depressants may increase sedative effects of Pramipexole. Risk C: Monitor

Pramlintide: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. These effects are specific to the GI tract. Risk X: Avoid

Procarbazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Prochlorperazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Prochlorperazine. Specifically, the risk of seizures may be increased. Risk C: Monitor

Promazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Promazine. Specifically, the risk of seizures may be increased. Risk C: Monitor

Promethazine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Promethazine. Risk C: Monitor

Propantheline: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Propantheline. Risk C: Monitor

Propiverine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

Psilocybin: Antidepressants may decrease therapeutic effects of Psilocybin. Risk C: Monitor

QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may increase QTc-prolonging effects of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor

QUEtiapine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of QUEtiapine. Specifically, the risk of seizures may be increased. Risk C: Monitor

QuiNIDine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

Ramosetron: Agents with Clinically Relevant Anticholinergic Effects may increase constipating effects of Ramosetron. Risk C: Monitor

Ramosetron: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Rasagiline: May increase serotonergic effects of Tricyclic Antidepressants. This could result in serotonin syndrome. Risk X: Avoid

Revefenacin: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Revefenacin. Risk X: Avoid

RifAMPin: May decrease serum concentration of Nortriptyline. Risk C: Monitor

Rifapentine: May decrease serum concentration of Nortriptyline. Risk C: Monitor

RisperiDONE: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of RisperiDONE. Specifically, the risk of seizures may be increased. Risk C: Monitor

Rivastigmine: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Rivastigmine. Rivastigmine may decrease therapeutic effects of Agents with Clinically Relevant Anticholinergic Effects. Management: Use of rivastigmine with an anticholinergic agent is not recommended unless clinically necessary. If the combination is necessary, monitor for reduced anticholinergic effects. Risk D: Consider Therapy Modification

Ropeginterferon Alfa-2b: CNS Depressants may increase adverse/toxic effects of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider Therapy Modification

ROPINIRole: CNS Depressants may increase sedative effects of ROPINIRole. Risk C: Monitor

Rotigotine: CNS Depressants may increase sedative effects of Rotigotine. Risk C: Monitor

Safinamide: May increase serotonergic effects of Tricyclic Antidepressants. This could result in serotonin syndrome. Risk X: Avoid

Scopolamine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Scopolamine. Risk C: Monitor

Secretin: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Secretin. Management: Avoid concomitant use of anticholinergic agents and secretin. Discontinue anticholinergic agents at least 5 half-lives prior to administration of secretin. Risk D: Consider Therapy Modification

Selegiline: May increase serotonergic effects of Tricyclic Antidepressants. This could result in serotonin syndrome. Risk X: Avoid

Serotonergic Agents (High Risk, Miscellaneous): Tricyclic Antidepressants may increase serotonergic effects of Serotonergic Agents (High Risk, Miscellaneous). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Serotonergic Non-Opioid CNS Depressants: Tricyclic Antidepressants may increase serotonergic effects of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Tricyclic Antidepressants may increase CNS depressant effects of Serotonergic Non-Opioid CNS Depressants. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and CNS depression when these agents are combined. Risk C: Monitor

Serotonergic Opioids (High Risk): May increase serotonergic effects of Tricyclic Antidepressants. This could result in serotonin syndrome. Tricyclic Antidepressants may increase CNS depressant effects of Serotonergic Opioids (High Risk). Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity and CNS depression. Risk D: Consider Therapy Modification

Serotonin 5-HT1D Receptor Agonists (Triptans): May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Serotonin/Norepinephrine Reuptake Inhibitor: May increase serotonergic effects of Tricyclic Antidepressants. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes when these agents are combined. Risk C: Monitor

Sertindole: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Sertindole. Specifically, the risk of seizures may be increased. Risk C: Monitor

Sertraline: May increase serotonergic effects of Tricyclic Antidepressants. Sertraline may increase serum concentration of Tricyclic Antidepressants. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and increased TCA concentrations/effects if these agents are combined. Risk C: Monitor

Sodium Phosphates: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Sodium Phosphates. Specifically, the risk of seizure or loss of consciousness may be increased in patients with significant sodium phosphate-induced fluid or electrolyte abnormalities. Risk C: Monitor

Sofpironium: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Sofpironium. Risk X: Avoid

St John's Wort: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. St John's Wort may decrease serum concentration of Serotonergic Agents (High Risk). Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Sulpiride: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Sulpiride. Specifically, the risk of seizures may be increased. Risk C: Monitor

Suvorexant: CNS Depressants may increase CNS depressant effects of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider Therapy Modification

Syrian Rue: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Thalidomide: CNS Depressants may increase CNS depressant effects of Thalidomide. Risk X: Avoid

Thiazide and Thiazide-Like Diuretics: Agents with Clinically Relevant Anticholinergic Effects may increase serum concentration of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor

Thioridazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Thioridazine. Specifically, the risk of seizures may be increased. Risk C: Monitor

Thiothixene: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Thiothixene. Risk C: Monitor

Thiothixene: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Thiothixene. Specifically, the risk of seizures may be increased. Risk C: Monitor

Thyroid Products: May increase arrhythmogenic effects of Tricyclic Antidepressants. Thyroid Products may increase stimulatory effects of Tricyclic Antidepressants. Risk C: Monitor

Tiapride: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Tiapride. Risk C: Monitor

Tiotropium: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Tiotropium. Risk X: Avoid

Tobacco (Smoked): May decrease serum concentration of Nortriptyline. Risk C: Monitor

Tolterodine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Tolterodine. Risk C: Monitor

Topiramate: Agents with Clinically Relevant Anticholinergic Effects may increase adverse/toxic effects of Topiramate. Risk C: Monitor

Tricyclic Antidepressants: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Tricyclic Antidepressants. Risk C: Monitor

Tricyclic Antidepressants: May increase anticholinergic effects of Tricyclic Antidepressants. Tricyclic Antidepressants may increase CNS depressant effects of Tricyclic Antidepressants. Tricyclic Antidepressants may increase serotonergic effects of Tricyclic Antidepressants. This could result in serotonin syndrome. Management: Monitor closely for increased TCA adverse effects, including serotonin syndrome/serotonin toxicity, CNS depression, and anticholinergic effects. Risk C: Monitor

Trifluoperazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Trifluoperazine. Specifically, the risk of seizures may be increased. Risk C: Monitor

Trimeprazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Trimethobenzamide: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Trimethobenzamide. Risk C: Monitor

Trospium: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Trospium. Risk C: Monitor

Umeclidinium: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid

Valerian: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Valproic Acid and Derivatives: May increase serum concentration of Tricyclic Antidepressants. Risk C: Monitor

Vasopressin: Drugs Suspected of Causing SIADH may increase therapeutic effects of Vasopressin. Specifically, the pressor and antidiuretic effects of vasopressin may be increased. Risk C: Monitor

Vilazodone: Tricyclic Antidepressants may increase serotonergic effects of Vilazodone. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) if these agents are combined. Risk C: Monitor

Vortioxetine: Tricyclic Antidepressants may increase serotonergic effects of Vortioxetine. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) if these agents are combined. Risk C: Monitor

Ziprasidone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Ziprasidone. Specifically, the risk of seizures may be increased. Risk C: Monitor

Ziprasidone: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor

Zolpidem: CNS Depressants may increase CNS depressant effects of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider Therapy Modification

Zuclopenthixol: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Zuclopenthixol. Risk C: Monitor

Zuclopenthixol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Zuclopenthixol. Specifically, the risk of seizures may be increased. Risk C: Monitor

Zuranolone: May increase CNS depressant effects of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider Therapy Modification

Reproductive Considerations

Evaluate pregnancy status prior to initiating treatment for depression in patients who could become pregnant. Treatment should not be withheld, but pharmacologic management may vary based on reproductive status, severity of illness, and history of antidepressant response (ACOG 2023; WFSBP [Dodd 2018]). When treating depression, tricyclic antidepressants are not first-line medications for use prior to conception in patients who are treatment naïve or who do not have a history of effective treatment. Patients effectively treated may continue their current medication when planning a pregnancy unless contraindications exist (BAP [McAllister-Williams 2017]). Management of mental health conditions in patients who could become pregnant should be based on a shared decision-making process that considers the possibility of pregnancy during treatment (ACOG 2023; BAP [McAllister-Williams 2017]; CANMAT [MacQueen 2016]).

Nortriptyline is effective for prevention of migraines. In general, preventive treatment for migraine in patients trying to become pregnant should be avoided. Options for patients planning a pregnancy should be considered as part of a shared decision-making process. Nonpharmacologic interventions should be considered initially. When needed, preventive treatment should be individualized considering the available safety data and needs of the patient should pregnancy occur. A gradual discontinuation of preventive medications is generally preferred when the decision is made to stop treatment prior to conception (ACOG 2022; AHS [Ailani 2021]).

Pregnancy Considerations

Nortriptyline and its metabolites cross the human placenta and can be detected in cord blood (Schoretsanitis 2021).

Outcome data following maternal use of tricyclic antidepressants (TCAs) including nortriptyline are available (Altshuler 1996; Bérard 2017; Cantarutti 2017; De Vries 2021; Ericson 1999; Huybrechts 2015; McDonagh 2014; McElhatton 1996). Study outcomes vary due to limited data, differences in study design, and confounders (Gentile 2014; Yonkers 2014).

Due to pregnancy-induced physiologic changes, some pharmacokinetic properties of nortriptyline may be altered. Nortriptyline clearance may be increased due to increased CYP2D6 activity particularly during the third trimester. Dose adjustments may be required. Therapeutic drug monitoring of nortriptyline is recommended monthly during pregnancy and 2 to 6 weeks postpartum to avoid toxicity and monitor efficacy (Deligiannidis 2014; Schoretsanitis 2020; Yue 2023).

Untreated and undertreated mental health conditions are associated with adverse pregnancy outcomes. Untreated or undertreated depression is associated with preterm birth, low birth weight, preeclampsia, postpartum depression, and impaired infant attachment (associated with long-term developmental effects). Discontinuing effective medications during pregnancy increases the risk of relapse. Management of mental health conditions should be made as part of a shared decision-making process (ACOG 2023). Patients effectively treated for depression prepregnancy may use the same medication during pregnancy unless contraindications exist (ACOG 2023; BAP [McAllister-Williams 2017]; CANMAT [MacQueen 2016]). Treatment should not be withheld or discontinued based only on pregnancy status (ACOG 2023). TCAs are not considered first-line medications for pregnant patients who are treatment naïve or who do not have a history of effective treatment with another medication (ACOG 2023; BAP [McAllister-Williams 2017]; CANMAT [MacQueen 2016]), but may be considered as an alternative (CANMAT [MacQueen 2016]). When medications are used, the lowest effective dose of a single agent is recommended. Optimize dosing prior to changing a medication or adding additional agents whenever possible. Close monitoring for symptom improvement with a validated screening tool during pregnancy is recommended. Manage side effects as needed (ACOG 2023).

In general, preventive treatment for migraine should be avoided during pregnancy. Options for pregnant patients should be considered as part of a shared decision-making process. Nonpharmacologic interventions should be considered initially. When needed, preventive treatment should be individualized considering the available safety data, the potential for adverse maternal and fetal events, and the needs of the patient (ACOG 2022; AHS [Ailani 2021]). Efficacy data of TCAs for migraine prevention in pregnancy are limited and use is not recommended (ACOG 2022). Nortriptyline may be used if other agents are ineffective or contraindicated, considering the risks and benefits of use (ACOG 2022; CHS [Pringsheim 2012]).

Data collection to monitor pregnancy and infant outcomes following exposure to antidepressant medications is ongoing. Encourage pregnant patients 45 years of age and younger with a history of psychiatric illness to enroll in the National Pregnancy Registry for Antidepressants (1-866-961-2388 or https://womensmentalhealth.org/research/pregnancyregistry/antidepressants).

Breastfeeding Considerations

Nortriptyline is present in breast milk.

Data related to the presence of nortriptyline in breast milk are available from a case report. The patient was taking nortriptyline 100 mg nightly during the second and third trimesters of pregnancy, then temporarily stopped for 2 weeks prior to a planned cesarean delivery. Breast milk was sampled 6 days postpartum following maternal administration of nortriptyline 125 mg daily, starting at day 1 postpartum. Breast milk concentrations of nortriptyline ranged from 0.177 to 0.404 mcg/mL. Based on the mean breast milk concentration, authors of the study calculated the estimated exposure of nortriptyline to the breastfeeding infant to be 27 mcg/kg/day (relative infant dose [RID] 1.3% based on the weight-adjusted maternal dose of a 60 kg person). Adverse events were not observed in the breastfeeding infant (Matheson 1988). In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000); however, some sources note breastfeeding should only be considered if the RID is <5% for psychotropic agents (Anderson 2021).

Nortriptyline and the E-10-hydroxynortriptyline and Z-10-hydroxynortriptyline metabolites have been detected in the serum of some infants exposed to nortriptyline via breast milk. Adverse events have not been observed (Weissman 2004; Wisner 2006).

Monitor infants exposed to psychotropic medication via breast milk for adverse effects (eg, over sedation, poor feeding) (BAP [McAllister-Williams 2017]).

Due to pregnancy-induced physiologic changes, the clearance of nortriptyline may be altered; maternal serum concentrations should be monitored closely immediately postpartum to prevent toxicity (Deligiannidis 2014; Schoretsanitis 2020; Yue 2023).

Patients effectively treated for depression with a tricyclic antidepressant (TCA) during pregnancy may continue their medication postpartum unless contraindications to breastfeeding exist. The presence and concentration of the drug in breast milk, efficacy of maternal treatment, and infant age should be considered when initiating a medication for the first time postpartum. When first initiating an antidepressant in a patient who is treatment naïve and breastfeeding, agents other than TCAs are preferred (ABM [Sriraman 2015]). Nortriptyline may be preferred when a TCA is needed (ABM [Sriraman 2015]; CANMAT [MacQueen 2016]).

In general, preventive treatment for migraine in breastfeeding patients should be avoided. When needed, therapy should be individualized considering the available safety data and needs of the patient (AHS [Ailani 2021]). Nortriptyline may be used if other agents are ineffective or contraindicated (CHS [Pringsheim 2012]).

Monitoring Parameters

Serum sodium in at-risk populations (as clinically indicated), blood pressure, heart pulse rate and ECG in older adults and patients with preexisting cardiac disease; blood glucose; weight and BMI; therapeutic blood levels (as clinically indicated); mental alertness; closely monitor all patients for depression, clinical worsening, suicidality, psychosis, or unusual changes in behavior (such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania), particularly during the initial 1 to 2 months of therapy or during periods of dosage adjustments (increased or decreases).

Reference Range

Timing of serum samples: Draw trough just before next dose (Hiemke 2018).

Therapeutic reference range: 50 to 170 ng/mL (SI: 189.9 to 645.5 nmol/L) (Hiemke 2018; manufacturer’s labeling).

Laboratory alert level: 300 ng/mL (SI: 1,139.1 nmol/L) (Hiemke 2018).

Mechanism of Action

Traditionally believed to increase the synaptic concentration of serotonin and/or norepinephrine in the central nervous system by inhibition of their reuptake by the presynaptic neuronal membrane. Inhibits the activity of histamine, 5-hydroxytryptamine, and acetylcholine. It increases the pressor effect of norepinephrine but blocks the pressor response of phenethylamine. However, additional receptor effects have been found including desensitization of adenyl cyclase, down regulation of beta-adrenergic receptors, and down regulation of serotonin receptors.

Pharmacokinetics (Adult Data Unless Noted)

Onset of action: Depression: Initial effects may be observed within 1 to 2 weeks of treatment, with continued improvements through 4 to 6 weeks (Papakostas 2006; Posternak 2005; Szegedi 2009).

Absorption: Oral: Rapid (Alexanderson 1972)

Distribution: Vd: 21.1 to 31.1 L/kg (Alexanderson 1972)

Protein binding: Extensively bound to plasma proteins (Alexanderson 1972)

Metabolism: Primarily hepatic; extensive first-pass effect (Rubin 1985)

Bioavailability: 46% to 70% (Rubin 1985)

Half-life elimination:

Adults: 14 to 51 hours (mean: 26 hours) (Dawling 1980)

Elderly: 23.5 to 79 hours (mean 45 hours) (Dawling 1980)

Time to peak, serum: 4 to 9 hours (Alexanderson 1972)

Excretion: Urine (as metabolites and small amounts of unchanged drug) (Alexanderson 1972)

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (AR) Argentina: Ateben;
  • (BD) Bangladesh: Avelin | Nortin;
  • (BR) Brazil: Cloridrato de nortriptilina | Nortrip | Pamelor;
  • (GB) United Kingdom: Nortriptyline;
  • (IE) Ireland: Aventyl;
  • (IT) Italy: Norcapto | Vividyl;
  • (PR) Puerto Rico: Aventyl | Nortriptyline HCL | Pamelor;
  • (SA) Saudi Arabia: Apo-nortriptyline;
  • (SG) Singapore: Apo-nortriptyline;
  • (TH) Thailand: Aventyl;
  • (TW) Taiwan: Aventyl;
  • (ZA) South Africa: Aventyl
  1. 2023 American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2023 updated AGS Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2023;71(7):2052-2081. doi:10.1111/jgs.18372 [PubMed 37139824]
  2. Ahlfors CE. Benzyl alcohol, kernicterus, and unbound bilirubin. J Pediatr. 2001;139(2):317-319. [PubMed 11487763]
  3. Ailani J, Burch RC, Robbins MS; Board of Directors of the American Headache Society. The American Headache Society consensus statement: update on integrating new migraine treatments into clinical practice. Headache. 2021;61(7):1021-1039. doi:10.1111/head.14153 [PubMed 34160823]
  4. Alampay MM, Haigney MC, Flanagan MC, Perito RM, Love KM, Grammer GG. Transcranial magnetic stimulation as an antidepressant alternative in a patient with Brugada syndrome and recurrent syncope. Mayo Clin Proc. 2014;89(11):1584-1587. doi:10.1016/j.mayocp.2014.08.010 [PubMed 25444490]
  5. Alexanderson B. Pharmacokinetics of nortriptyline in man after single and multiple oral doses: the predictability of steady-state plasma concentrations from single-dose plasma-level data. Eur J Clin Pharmacol. 1972;4(2):82-91. [PubMed 4655685]
  6. Altshuler LL, Cohen L, Szuba MP, Burt VK, Gitlin M, Mintz J. Pharmacologic management of psychiatric illness during pregnancy: dilemmas and guidelines. Am J Psychiatry. 1996;153(5):592-606. doi:10.1176/ajp.153.5.592 [PubMed 8615404]
  7. American College of Obstetricians and Gynecologists (ACOG). Headaches in pregnancy and postpartum: ACOG clinical practice guideline no. 3. Obstet Gynecol. 2022;139(5):944-972. doi:10.1097/AOG.0000000000004766 [PubMed 35576364]
  8. American College of Obstetricians and Gynecologists (ACOG). Treatment and management of mental health conditions during pregnancy and postpartum: ACOG Clinical Practice Guideline No. 5. Obstet Gynecol. 2023;141(6):1262-1288. doi:10.1097/AOG.0000000000005202 [PubMed 37486661]
  9. American College of Obstetricians and Gynecologists (ACOG). Use of psychiatric medications during pregnancy and lactation: ACOG clinical practice guideline no. 92. Obstet Gynecol. 2008;111(4):1001-1020. doi:10.1097/AOG.0b013e31816fd910 [PubMed 18378767]
  10. American Psychiatric Association (APA). Practice guideline for the treatment of patients with major depressive disorder. 3rd ed. http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf. Published October 2010. Accessed May 11, 2021.
  11. American Society of Anesthesiologists Task Force on Chronic Pain Management; American Society of Regional Anesthesia and Pain Medicine. Practice guidelines for chronic pain management: an updated report by the American Society of Anesthesiologists Task Force on Chronic Pain Management and the American Society of Regional Anesthesia and Pain Medicine. Anesthesiology. 2010;112(4):810-833. doi:10.1097/ALN.0b013e3181c43103 [PubMed 20124882]
  12. Anderson PO. Antidepressants and breastfeeding. Breastfeed Med. 2021;16(1):5-7. doi:10.1089/bfm.2020.0350 [PubMed 33237799]
  13. Anderson PO, Sauberan JB. Modeling drug passage into human milk. Clin Pharmacol Ther. 2016;100(1):42-52. [PubMed 27060684]
  14. Asberg M, Germanis M. Ophthalmological effects of nortriptyline--relationship to plasma level. Pharmacology. 1972;7(5):349-356. doi:10.1159/000136309 [PubMed 4566251]
  15. Attal N, Cruccu G, Baron R, et al; European Federation of Neurological Societies. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol. 2010;17(9):1113-1123; e67-e88. [PubMed 20402746]
  16. Bai AD, McKenna S, Wise H, Loeb M, Gill SS. Association of linezolid with risk of serotonin syndrome in patients receiving antidepressants. JAMA Netw Open. 2022;5(12):e2247426. doi:10.1001/jamanetworkopen.2022.47426 [PubMed 36534400]
  17. Bangash HK, Finch T, Petronic-Rosic V, Sethi A, Abramsohn E, Lindau ST. Pityriasis rosea-like drug eruption due to nortriptyline in a patient with vulvodynia. J Low Genit Tract Dis. 2013;17(2):226-229. doi:10.1097/LGT.0b013e31825d7c5f [PubMed 23343697]
  18. Bardai A, Amin AS, Blom MT, et al. Sudden cardiac arrest associated with use of a non-cardiac drug that reduces cardiac excitability: evidence from bench, bedside, and community. Eur Heart J. 2013;34(20):1506-1516. doi:10.1093/eurheartj/eht054 [PubMed 23425522]
  19. Barohn RJ, Gajewski B, Pasnoor M, et al; Patient Assisted Intervention for Neuropathy: Comparison of Treatment in Real Life Situations (PAIN-CONTRoLS) Study Team. Patient assisted intervention for neuropathy: comparison of treatment in real life situations (PAIN-CONTRoLS): Bayesian adaptive comparative effectiveness randomized trial. JAMA Neurol. 2021;78(1):68-76. doi:10.1001/jamaneurol.2020.2590 [PubMed 32809014]
  20. Bartlett D. Drug-induced serotonin syndrome. Crit Care Nurse. 2017;37(1):49-54. doi:10.4037/ccn2017169 [PubMed 28148614]
  21. Bauer M, Pfennig A, Severus E, Whybrow PC, Angst J, Möller HJ; World Federation of Societies of Biological Psychiatry. Task Force on Unipolar Depressive Disorders. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry. 2013;14(5):334-385. doi:10.3109/15622975.2013.804195 [PubMed 23879318]
  22. Bauer M, Severus E, Köhler S, Whybrow PC, Angst J, Möller HJ; WFSBP Task Force on Treatment Guidelines for Unipolar Depressive Disorders. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders. Part 2: maintenance treatment of major depressive disorder-update 2015. World J Biol Psychiatry. 2015;16(2):76-95. doi: 10.3109/15622975.2014.1001786. [PubMed 25677972]
  23. Bauer M, Whybrow PC, Anst J, et al. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders, Part 2: Maintenance treatment of major depressive disorder and treatment of chronic depressive disorders and subthreshold depressions. World J Biol Psychiatry. 2002;3(2):69-86. [PubMed 12479080]
  24. Bendtsen L, Evers S, Linde M, Mitsikostas DD, Sandrini G, Schoenen J; EFNS. EFNS guideline on the treatment of tension-type headache - report of an EFNS task force. Eur J Neurol. 2010;17(11):1318-1325. doi:10.1111/j.1468-1331.2010.03070.x [PubMed 20482606]
  25. Bendtsen L, Jensen R, Olesen J. A non-selective (amitriptyline), but not a selective (citalopram), serotonin reuptake inhibitor is effective in the prophylactic treatment of chronic tension-type headache. J Neurol Neurosurg Psychiatry. 1996;61(3):285-290. doi:10.1136/jnnp.61.3.285 [PubMed 8795600]
  26. Bérard A, Zhao JP, Sheehy O. Antidepressant use during pregnancy and the risk of major congenital malformations in a cohort of depressed pregnant women: an updated analysis of the Quebec Pregnancy Cohort. BMJ Open. 2017;7(1):e013372. doi:10.1136/bmjopen-2016-013372 [PubMed 28082367]
  27. Biringer E, Rongve A, Lund A. A review of modern antidepressants' effects on neurocognitive function. Curr Psych Rev. 2009;5(3):1-11.
  28. Birmaher B, Brent D, Bernet W, et al; AACAP Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with depressive disorders. J Am Acad Child Adolesc Psychiatry. 2007;46(11):1503-1526. doi:10.1097/chi.0b013e318145ae1c [PubMed 18049300]
  29. Blonde L, Umpierrez GE, Reddy SS, et al. American Association of Clinical Endocrinology clinical practice guideline: developing a diabetes mellitus comprehensive care plan-2022 update. Endocr Pract. 2022;28(10):923-1049. doi:10.1016/j.eprac.2022.08.002 [PubMed 35963508]
  30. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112-1120. Erratum in: N Engl J Med. 2007;356(23):2437. Erratum in: N Engl J Med. 2009;361(17):1714. doi:10.1056/NEJMra041867 [PubMed 15784664]
  31. Braak B, Klooker TK, Wouters MM, Lei A, van den Wijngaard RM, Boeckxstaens GE. Randomised clinical trial: the effects of amitriptyline on drinking capacity and symptoms in patients with functional dyspepsia, a double-blind placebo-controlled study. Aliment Pharmacol Ther. 2011;34(6):638-648. doi:10.1111/j.1365-2036.2011.04775.x [PubMed 21767283]
  32. Briggs R, Carey D, McNicholas T, et al. The association between antidepressant use and orthostatic hypotension in older people: a matched cohort study. J Am Soc Hypertens. 2018;12(8):597-604.e1. doi:10.1016/j.jash.2018.06.002 [PubMed 29937420]
  33. Burch R. Antidepressants for preventive treatment of migraine. Curr Treat Options Neurol. 2019;21(4):18. doi:10.1007/s11940-019-0557-2 [PubMed 30895388]
  34. Butterfield JM, Lawrence KR, Reisman A, Huang DB, Thompson CA, Lodise TP. Comparison of serotonin toxicity with concomitant use of either linezolid or comparators and serotonergic agents: an analysis of phase III and IV randomized clinical trial data. J Antimicrob Chemother. 2012;67(2):494-502. doi:10.1093/jac/dkr467 [PubMed 22139199]
  35. Cantarutti A, Merlino L, Giaquinto C, Corrao G. Use of antidepressant medication in pregnancy and adverse neonatal outcomes: a population-based investigation. Pharmacoepidemiol Drug Saf. 2017;26(9):1100-1108. doi:10.1002/pds.4242 [PubMed 28594145]
  36. Centers for Disease Control and Prevention (CDC). Neonatal deaths associated with use of benzyl alcohol—United States. MMWR Morb Mortal Wkly Rep. 1982;31(22):290-291. http://www.cdc.gov/mmwr/preview/mmwrhtml/00001109.htm [PubMed 6810084]
  37. Chandra K, Shafiq N, Pandhi P, Gupta S, Malhotra S. Gabapentin versus nortriptyline in post-herpetic neuralgia patients: a randomized, double-blind clinical trial—the GONIP Trial. Int J Clin Pharmacol Ther. 2006;44(8):358-363. [PubMed 16961166]
  38. Chang L, Sultan S, Lembo A, Verne GN, Smalley W, Heidelbaugh JJ. AGA clinical practice guideline on the pharmacological management of irritable bowel syndrome with constipation. Gastroenterology. 2022;163(1):118-136. doi:10.1053/j.gastro.2022.04.016 [PubMed 35738724]
  39. Cheung AH, Zuckerbrot RA, Jensen PS, Laraque D, Stein REK; GLAD-PC Steering Group. Guidelines for adolescent depression in primary care (GLAD-PC): part II. Treatment and ongoing management. Pediatrics. 2018;141(3):e20174082. doi:10.1542/peds.2017-4082 [PubMed 29483201]
  40. Chew ML, Mulsant BH, Pollock BG, et al. Anticholinergic activity of 107 medications commonly used by older adults. J Am Geriatr Soc. 2008;56(7):1333-1341. doi:10.1111/j.1532-5415.2008.01737.x [PubMed 18510583]
  41. Costagliola C, Parmeggiani F, Semeraro F, Sebastiani A. Selective serotonin reuptake inhibitors: a review of its effects on intraocular pressure. Curr Neuropharmacol. 2008;6(4):293-310. doi:10.2174/157015908787386104 [PubMed 19587851]
  42. Davidoff K, Heneghan C, Wolfe J, Ullrich C. Pediatric palliative care. In: Kliegman RM, St Geme JW, Blum NJ, et al, eds. Nelson Textbook of Pediatrics. 22nd ed. Elsevier; 2025:chap 8.
  43. Dawling S, Crome P, Braithwaite R. Pharmacokinetics of Single Oral Doses of Nortriptyline in Depressed Elderly Hospital Patients and Young Healthy Volunteers. Clin Pharmacokinet. 1980;5(4):394-401. [PubMed 6994983]
  44. Dawling S, Lynn K, Rosser R, Braithwaite R. Nortriptyline metabolism in chronic renal failure: metabolite elimination. Clin Pharmacol Ther. 1982;32(3):322-329. doi:10.1038/clpt.1982.167 [PubMed 7105623]
  45. Dawling S, Lynn K, Rosser R, Braithwaite R. The pharmacokinetics of nortriptyline in patients with chronic renal failure. Br J Clin Pharmacol. 1981;12(1):39-45. doi:10.1111/j.1365-2125.1981.tb01852.x [PubMed 7248140]
  46. Deligiannidis KM, Byatt N, Freeman MP. Pharmacotherapy for mood disorders in pregnancy: a review of pharmacokinetic changes and clinical recommendations for therapeutic drug monitoring. J Clin Psychopharmacol. 2014;34(2):244-255. doi:10.1097/JCP.0000000000000087 [PubMed 24525634]
  47. De Picker L, Van Den Eede F, Dumont G, et al. Antidepressants and the risk of hyponatremia: a class-by-class review of literature. Psychosomatics. 2014;55(6):536-547. doi: 10.1016/j.psym.2014.01.010. [PubMed 25262043]
  48. Desai MJ, Saini V, Saini S. Myofascial pain syndrome: a treatment review. Pain Ther. 2013;2(1):21-36. doi:10.1007/s40122-013-0006-y [PubMed 25135034]
  49. De Vries C, Gadzhanova S, Sykes MJ, Ward M, Roughead E. A systematic review and meta-analysis considering the risk for congenital heart defects of antidepressant classes and individual antidepressants. Drug Saf. 2021;44(3):291-312. doi:10.1007/s40264-020-01027-x [PubMed 33354752]
  50. Dhippayom T, Chaiyakunapruk N, Jongchansittho T. Safety of nortriptyline at equivalent therapeutic doses for smoking cessation: a systematic review and meta-analysis. Drug Saf. 2011;34(3):199-210. doi:10.2165/11585950-000000000-00000 [PubMed 21332244]
  51. Dilsaver SC. Withdrawal phenomena associated with antidepressant and antipsychotic agents. Drug Saf. 1994;10(2):103-114. doi:10.2165/00002018-199410020-00002 [PubMed 7912078]
  52. Dodd S, Malhi GS, Tiller J, et al. A consensus statement for safety monitoring guidelines of treatments for major depressive disorder. Aust N Z J Psychiatry. 2011;45(9):712-725. doi:10.3109/00048674.2011.595686 [PubMed 21888608]
  53. Dodd S, Mitchell PB, Bauer M, et al. Monitoring for antidepressant-associated adverse events in the treatment of patients with major depressive disorder: an international consensus statement. World J Biol Psychiatry. 2018;19(5):330-348. doi:10.1080/15622975.2017.1379609 [PubMed 28984491]
  54. Dopheide JA. Recognizing and treating depression in children and adolescents. Am J Health Syst Pharm. 2006;63(3):233-243. [PubMed 16434782]
  55. Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The hunter serotonin toxicity criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM. 2003;96(9):635-642. doi:10.1093/qjmed/hcg109 [PubMed 12925718]
  56. ElSayed NA, Aleppo G, Aroda VR, et al; American Diabetes Association. 12. Retinopathy, neuropathy, and foot care: standards of care in diabetes-2023. Diabetes Care. 2023;46(suppl 1):S203-S215. doi:10.2337/dc23-S012 [PubMed 36507636]
  57. Ericson A, Källén B, Wiholm B. Delivery outcome after the use of antidepressants in early pregnancy. Eur J Clin Pharmacol. 1999;55(7):503-508. doi:10.1007/s002280050664 [PubMed 10501819]
  58. Expert opinion. Senior Renal Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
  59. Eyler RF, Unruh ML, Quinn DK, Vilay AM. Psychotherapeutic agents in end-stage renal disease. Semin Dial. 2015;28(4):417-426. doi:10.1111/sdi.12370 [PubMed 25857865]
  60. Fava M. Prospective studies of adverse events related to antidepressant discontinuation. J Clin Psychiatry. 2006;67(Suppl 4):14-21. [PubMed 16683858]
  61. Feldman EL. Management of diabetic neuropathy. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed June 22, 2022.
  62. Fenske JN, Schwenk TL. Obsessive compulsive disorder: diagnosis and management. Am Fam Physician. 2009;80(3):239-245. [PubMed 19621834]
  63. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162-173. doi:10.1016/S1474-4422(14)70251-0 [PubMed 25575710]
  64. Frazier R, Li BUK, Venkatesan T. Diagnosis and management of cyclic vomiting syndrome: a critical review. Am J Gastroenterol. 2023;118(7):1157-1167. doi:10.14309/ajg.0000000000002216 [PubMed 36791365]
  65. Friedman RA, Leon AC. Expanding the black box - depression, antidepressants, and the risk of suicide. N Engl J Med. 2007;356(23):2343-2346. doi:10.1056/NEJMp078015 [PubMed 17485726]
  66. Funai Y, Funao T, Ikenaga K, Takahashi R, Hase I, Nishikawa K. Use of tricyclic antidepressants as analgesic adjuvants results in nonhazardous prolongation of the QTc interval. Osaka City Med J. 2014;60(1):11-19. [PubMed 25272563]
  67. Gastó C, Navarro V, Marcos T, Portella MJ, Torra M, Rodamilans M. Single-blind comparison of venlafaxine and nortriptyline in elderly major depression. J Clin Psychopharmacol. 2003;23(1):21-26. doi:10.1097/00004714-200302000-00004 [PubMed 12544371]
  68. Geller B, Cooper TB, Carr LG, Warham JE, Rodriguez A. Prospective study of scheduled withdrawal from nortriptyline in children and adolescents. J Clin Psychopharmacol. 1987;7(4):252-254. [PubMed 3624507]
  69. Gentile S. Tricyclic antidepressants in pregnancy and puerperium. Expert Opin Drug Saf. 2014;13(2):207-225. doi:10.1517/14740338.2014.869582 [PubMed 24383525]
  70. Georgotas A, McCue RE, Friedman E, Cooper TB. A placebo-controlled comparison of the effect of nortriptyline and phenelzine on orthostatic hypotension in elderly depressed patients. J Clin Psychopharmacol. 1987;7(6):413-416. [PubMed 3323263]
  71. Giardina EG, Johnson LL, Vita J, Bigger JT Jr, Brem RF. Effect of imipramine and nortriptyline on left ventricular function and blood pressure in patients treated for arrhythmias. Am Heart J. 1985;109(5 pt 1):992-998. doi:10.1016/0002-8703(85)90240-6 [PubMed 3993532]
  72. Gibbons RD, Brown CH, Hur K, et al. Early evidence on the effects of regulators' suicidality warnings on SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry. 2007;164(9):1356-1363. doi:10.1176/appi.ajp.2007.07030454 [PubMed 17728420]
  73. Gibbons RD, Brown CH, Hur K, Davis J, Mann JJ. Suicidal thoughts and behavior with antidepressant treatment: reanalysis of the randomized placebo-controlled studies of fluoxetine and venlafaxine. Arch Gen Psychiatry. 2012;69(6):580-587. Erratum in: Arch Gen Psychiatry. 2013 Aug;70(8):881. doi:10.1001/archgenpsychiatry.2011.2048 [PubMed 22309973]
  74. Gilron I, Bailey JM, Tu D, Holden RR, Jackson AC, Houlden RL. Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial. Lancet. 2009;374(9697):1252-1261. [PubMed 19796802]
  75. Gjerdingen D. The effectiveness of various postpartum depression treatments and the impact of antidepressant drugs on nursing infants. J Am Board Fam Pract. 2003;16(5):372-382. [PubMed 14645327]
  76. Glassman AH, Preud'homme XA. Review of the cardiovascular effects of heterocyclic antidepressants. J Clin Psychiatry. 1993;54 Suppl:16-22. [PubMed 8444830]
  77. Graff-Radford SB. Myofascial pain: diagnosis and management. Curr Pain Headache Rep. 2004;8(6):463-467. doi:10.1007/s11916-004-0068-y [PubMed 15509460]
  78. Grunze H, Vieta E, Goodwin GM, et al; Members of the WFSBP Task Force on Bipolar Affective Disorders working on this topic. The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: Acute and long-term treatment of mixed states in bipolar disorder. World J Biol Psychiatry. 2018;19(1):2-58. doi: 10.1080/15622975.2017.1384850. [PubMed 29098925]
  79. Haddad PM. Antidepressant discontinuation syndromes. Drug Saf. 2001;24(3):183-197. [PubMed 11347722]
  80. Hall SM, Humfleet GL, Reus VI, Muñoz RF, Cullen J. Extended nortriptyline and psychological treatment for cigarette smoking. Am J Psychiatry. 2004;161(11):2100-2107. doi:10.1176/appi.ajp.161.11.2100 [PubMed 15514412]
  81. Hall SM, Humfleet GL, Reus VI, Muñoz RF, Hartz DT, Maude-Griffin R. Psychological intervention and antidepressant treatment in smoking cessation. Arch Gen Psychiatry. 2002;59(10):930-936. doi:10.1001/archpsyc.59.10.930 [PubMed 12365880]
  82. Hall SM, Reus VI, Muñoz RF, et al. Nortriptyline and cognitive-behavioral therapy in the treatment of cigarette smoking. Arch Gen Psychiatry. 1998;55(8):683-690. doi:10.1001/archpsyc.55.8.683 [PubMed 9707377]
  83. Hammad TA, Laughren T, Racoosin J. Suicidality in pediatric patients treated with antidepressant drugs. Arch Gen Psychiatry. 2006;63(3):332-339. doi:10.1001/archpsyc.63.3.332 [PubMed 16520440]
  84. Hathaway EE, Walkup JT, Strawn JR. Antidepressant Treatment Duration in Pediatric Depressive and Anxiety Disorders: How Long is Long Enough? Curr Probl Pediatr Adolesc Health Care. 2018;48(2):31-39. [PubMed 29337001]
  85. Hauer J, Houtrow AJ; Section on Hospice and Palliative Medicine, Council on Children with Disabilities. Pain assessment and treatment in children with significant impairment of the central nervous system. Pediatrics. 2017;139(6):e20171002. doi:10.1542/peds.2017-1002 [PubMed 28562301]
  86. Haviv Y, Rettman A, Aframian D, Sharav Y, Benoliel R. Myofascial pain: an open study on the pharmacotherapeutic response to stepped treatment with tricyclic antidepressants and gabapentin. J Oral Facial Pain Headache. 2015;29(2):144-151. doi:10.11607/ofph.1408 [PubMed 25905532]
  87. Hejazi RA, Reddymasu SC, Namin F, Lavenbarg T, Foran P, McCallum RW. Efficacy of tricyclic antidepressant therapy in adults with cyclic vomiting syndrome: a two-year follow-up study. J Clin Gastroenterol. 2010;44(1):18-21. doi:10.1097/MCG.0b013e3181ac6489 [PubMed 20027010]
  88. Hetrick SE, McKenzie JE, Cox GR, Simmons MB, Merry SN. Newer generation antidepressants for depressive disorders in children and adolescents. Cochrane Database Syst Rev. 2012;11:CD004851. doi:10.1002/14651858.CD004851.pub3 [PubMed 23152227]
  89. Hiemke C, Bergemann N, Clement HW, et al. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: update 2017. Pharmacopsychiatry. 2018;51(1-02):9-62. doi: 10.1055/s-0043-116492. [PubMed 28910830]
  90. Hinds NP, Hillier CE, Wiles CM. Possible serotonin syndrome arising from an interaction between nortriptyline and selegiline in a lady with parkinsonism. J Neurol. 2000;247(10):811. doi:10.1007/s004150070101 [PubMed 11127542]
  91. Hirsch M, Birnbaum RJ. Discontinuing antidepressant medications in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed January 5, 2024.
  92. Hirsch M, Birnbaum RJ. Switching antidepressant medications in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed November 30, 2022b.
  93. Hirsch M, Birnbaum RJ. Tricyclic and tetracyclic drugs: pharmacology, administration and side effects. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed June 22, 2022a.
  94. Hoff AL, Shukla S, Helms P, et al. The effects of nortriptyline on cognition in elderly depressed patients. J Clin Psychopharmacol. 1990;10(3):231-232. doi:10.1097/00004714-199006000-00025 [PubMed 2376622]
  95. Holroyd KA, O'Donnell FJ, Stensland M, Lipchik GL, Cordingley GE, Carlson BW. Management of chronic tension-type headache with tricyclic antidepressant medication, stress management therapy, and their combination: a randomized controlled trial. JAMA. 2001;285(17):2208-2215. doi:10.1001/jama.285.17.2208 [PubMed 11325322]
  96. Hubbard R, Farrington P, Smith C, Smeeth L, Tattersfield A. Exposure to tricyclic and selective serotonin reuptake inhibitor antidepressants and the risk of hip fracture. Am J Epidemiol. 2003;158(1):77-84. doi:10.1093/aje/kwg114 [PubMed 12835289]
  97. Huybrechts KF, Bateman BT, Palmsten K, et al. Antidepressant use late in pregnancy and risk of persistent pulmonary hypertension of the newborn. JAMA. 2015;313(21):2142-2151. doi:10.1001/jama.2015.5605 [PubMed 26034955]
  98. "Inactive" ingredients in pharmaceutical products: update (subject review). American Academy of Pediatrics (AAP) Committee on Drugs. Pediatrics. 1997;99(2):268-278. [PubMed 9024461]
  99. Isaac Z. Management of nonradicular neck pain in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed June 22, 2022.
  100. Ito S. Drug therapy for breast-feeding women. N Engl J Med. 2000;343(2):118-126. [PubMed 10891521]
  101. Jacob S, Spinler SA. Hyponatremia associated with selective serotonin-reuptake inhibitors in older adults. Ann Pharmacother. 2006;40(9):1618-1622. doi:10.1345/aph.1G293 [PubMed 16896026]
  102. Jha MK, Rush AJ, Trivedi MH. When discontinuing SSRI antidepressants Is a challenge: Management tips. Am J Psychiatry. 2018;175(12):1176-1184. doi:10.1176/appi.ajp.2018.18060692 [PubMed 30501420]
  103. Karkow DC, Kauer JF, Ernst EJ. Incidence of serotonin syndrome with combined use of linezolid and serotonin reuptake inhibitors compared with linezolid monotherapy. J Clin Psychopharmacol. 2017;37(5):518-523. doi:10.1097/JCP.0000000000000751 [PubMed 28796019]
  104. Kellogg Spadt S, Kingsberg S. Vulvar pain of unknown cause (vulvodynia): treatment. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed November 30, 2022.
  105. Khade A, Bashir MS, Kale AS, Turankar A. Study of the effect of nortriptyline and fluvoxamine on psychomotor functions in healthy volunteers. Indian J Psychol Med. 2010;32(2):104-107. doi:10.4103/0253-7176.78506 [PubMed 21716778]
  106. Khan A, Khan S, Kolts R, Brown WA. Suicide rates in clinical trials of SSRIs, other antidepressants, and placebo: analysis of FDA reports. Am J Psychiatry. 2003;160(4):790-792. doi:10.1176/appi.ajp.160.4.790 [PubMed 12668373]
  107. Khoromi S, Cui L, Nackers L, Max MB. Morphine, nortriptyline and their combination vs. placebo in patients with chronic lumbar root pain. Pain. 2007;130(1-2):66-75. doi:10.1016/j.pain.2006.10.029 [PubMed 17182183]
  108. Kirkham J, Seitz D. Evidence of ocular side effects of SSRIs and new warnings. Evid Based Ment Health. 2017;20(1):27. doi:10.1136/eb-2016-102528 [PubMed 27993931]
  109. Knegtering H, Eijck M, Huijsman A. Effects of antidepressants on cognitive functioning of elderly patients. A review. Drugs Aging. 1994;5(3):192-199. doi:10.2165/00002512-199405030-00005 [PubMed 7803947]
  110. Kok RM, Nolen WA, Heeren TJ. Venlafaxine versus nortriptyline in the treatment of elderly depressed inpatients: a randomised, double-blind, controlled trial. Int J Geriatr Psychiatry. 2007;22(12):1247-1254. doi:10.1002/gps.1823 [PubMed 17562523]
  111. Kufel WD, Parsels KA, Blaine BE, Steele JM, Seabury RW, Asiago-Reddy EA. Real-world evaluation of linezolid-associated serotonin toxicity with and without concurrent serotonergic agents. Int J Antimicrob Agents. 2023;62(1):106843. doi:10.1016/j.ijantimicag.2023.106843 [PubMed 37160238]
  112. Lacy BE, Pimentel M, Brenner DM, et al. ACG clinical guideline: management of irritable bowel syndrome. Am J Gastroenterol. 2021;116(1):17-44. doi:10.14309/ajg.0000000000001036 [PubMed 33315591]
  113. Lembo A, Sultan S, Chang L, Heidelbaugh JJ, Smalley W, Verne GN. AGA clinical practice guideline on the pharmacological management of irritable bowel syndrome with diarrhea. Gastroenterology. 2022;163(1):137-151. doi:10.1053/j.gastro.2022.04.017 [PubMed 35738725]
  114. Leon AC. The revised warning for antidepressants and suicidality: unveiling the black box of statistical analyses. Am J Psychiatry. 2007;164(12):1786-1789. doi:10.1176/appi.ajp.2007.07050775 [PubMed 18056231]
  115. Li B UK. Cyclic vomiting syndrome. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed June 22, 2022.
  116. Lieberman JA, Cooper TB, Suckow RF, et al. Tricyclic antidepressant and metabolite levels in chronic renal failure. Clin Pharmacol Ther. 1985;37(3):301-307. doi:10.1038/clpt.1985.44 [PubMed 3971655]
  117. Lien YH. Antidepressants and Hyponatremia. Am J Med. 2018;131(1):7-8. doi:10.1016/j.amjmed.2017.09.002 [PubMed 28923523]
  118. Liu WQ, Kanungo A, Toth C. Equivalency of tricyclic antidepressants in open-label neuropathic pain study. Acta Neurol Scand. 2014;129(2):132-141. doi:10.1111/ane.12169 [PubMed 23937282]
  119. Longstreth GF, Lacy BE. Functional dyspepsia in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed January 19, 2023.
  120. MacQueen GM, Frey BN, Ismail Z, et al; CANMAT Depression Work Group. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 6. Special populations: youth, women, and the elderly. Can J Psychiatry. 2016;61(9):588-603. doi:10.1177/0706743716659276 [PubMed 27486149]
  121. Madsen T, Buttenschøn HN, Uher R, et al. Trajectories of suicidal ideation during 12 weeks of escitalopram or nortriptyline antidepressant treatment among 811 patients with major depressive disorder. J Clin Psychiatry. 2019;80(4):18m12575. doi:10.4088/JCP.18m12575 [PubMed 31318184]
  122. Mannesse CK, Jansen PA, Van Marum RJ, et al. Characteristics, prevalence, risk factors, and underlying mechanism of hyponatremia in elderly patients treated with antidepressants: a cross-sectional study. Maturitas. 2013;76(4):357-363. doi:10.1016/j.maturitas.2013.08.010 [PubMed 24094459]
  123. Marraccini RL, Reynolds CF 3rd, Houck PR, et al. A double-blind, placebo-controlled assessment of nortriptyline's side-effects during 3-year maintenance treatment in elderly patients with recurrent major depression. Int J Geriatr Psychiatry. 1999;14(12):1014-1018. [PubMed 10607968]
  124. Mason PJ, Morris VA, Balcezak TJ. Serotonin syndrome. Presentation of 2 cases and review of the literature. Medicine (Baltimore). 2000;79(4):201-209. doi:10.1097/00005792-200007000-00001 [PubMed 10941349]
  125. Matheson I, Skjaeraasen J. Milk concentrations of flupenthixol, nortriptyline and zuclopenthixol and between-breast differences in two patients. Eur J Clin Pharmacol. 1988;35(2):217-220. [PubMed 3191943]
  126. Mauri MC, Fiorentini A, Paletta S, Altamura AC. Pharmacokinetics of antidepressants in patients with hepatic impairment. Clin Pharmacokinet. 2014;53(12):1069-1081. doi:10.1007/s40262-014-0187-5 [PubMed 25248846]
  127. McAllister-Williams RH, Baldwin DS, Cantwell R, et al. British Association for Psychopharmacology consensus guidance on the use of psychotropic medication preconception, in pregnancy and postpartum 2017. J Psychopharmacol. 2017;31(5):519-552. doi:10.1177/0269881117699361 [PubMed 28440103]
  128. McCue RE, Georgotas A, Suckow RF, Cooper TB. 10-Hydroxynortriptyline and treatment effects in elderly depressed patients. J Neuropsychiatry Clin Neurosci. 1989;1(2):176-180. doi:10.1176/jnp.1.2.176 [PubMed 2521060]
  129. McDonagh MS, Matthews A, Phillipi C, et al. Depression drug treatment outcomes in pregnancy and the postpartum period: a systematic review and meta-analysis. Obstet Gynecol. 2014;124(3):526-534. doi:10.1097/AOG.0000000000000410 [PubMed 25004304]
  130. McElhatton PR, Garbis HM, Eléfant E, et al. The outcome of pregnancy in 689 women exposed to therapeutic doses of antidepressants. A collaborative study of the European Network of Teratology Information Services (ENTIS). Reprod Toxicol. 1996;10(4):285-294. doi:10.1016/0890-6238(96)00057-3 [PubMed 8829251]
  131. Mehta NR, Keith DK. Temporomandibular disorders in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed June 22, 2022.
  132. Moayyedi P, Lacy BE, Andrews CN, Enns RA, Howden CW, Vakil N. ACG and CAG clinical guideline: management of dyspepsia. Am J Gastroenterol. 2017;112(7):988-1013. doi:10.1038/ajg.2017.154 [PubMed 28631728]
  133. Moulin DE, Clark AJ, Gilron I, et al; Canadian Pain Society. Pharmacological management of chronic neuropathic pain - consensus statement and guidelines from the Canadian Pain Society. Pain Res Manag. 2007;12(1):13-21. [PubMed 17372630]
  134. Mullen S. Major depressive disorder in children and adolescents. Ment Health Clin. 2018;8(6):275-283. doi:10.9740/mhc.2018.11.275 [PubMed 30397569]
  135. Mullish BH, Kabir MS, Thursz MR, Dhar A. Review article: depression and the use of antidepressants in patients with chronic liver disease or liver transplantation. Aliment Pharmacol Ther. 2014;40(8):880-892. doi:10.1111/apt.12925 [PubMed 25175904]
  136. Nagler EV, Webster AC, Vanholder R, Zoccali C. Antidepressants for depression in stage 3-5 chronic kidney disease: a systematic review of pharmacokinetics, efficacy and safety with recommendations by European Renal Best Practice (ERBP). Nephrol Dial Transplant. 2012;27(10):3736-3745. doi:10.1093/ndt/gfs295 [PubMed 22859791]
  137. Narita M, Tsuji BT, Yu VL. Linezolid-associated peripheral and optic neuropathy, lactic acidosis, and serotonin syndrome. Pharmacotherapy. 2007;27(8):1189-1197. doi:10.1592/phco.27.8.1189 [PubMed 17655517]
  138. National Collaborating Centre for Mental Health (NCCMH). Depression: The Treatment and Management of Depression in Adults (Updated Edition). National Institute for Health & Clinical Excellence (NICE). 2010. [PubMed 22132433]
  139. National Collaborating Centre for Nursing and Supportive Care; National Institute for Health and Clinical Excellence. Clinical practice guideline: irritable bowel syndrome in adults: diagnosis and management of irritable bowel syndrome in primary care. https://www.nice.org.uk/guidance/cg61/evidence/full-guidance-196701661. Published February 2008. Updated March 2017. Accessed June 3, 2021.
  140. National Guideline Centre (UK). Attention deficit hyperactivity disorder: diagnosis and management. London: National Institute for Health and Care Excellence (NICE) (UK); March 2018. [PubMed 29634174]
  141. Nortriptyline [prescribing information]. North Wales, PA: Teva Pharmaceuticals Inc; May 2015.
  142. Nortriptyline hydrochloride oral solution, USP [prescribing information]. Greenville, SC: Pharmaceutical Associates Inc; March 2023.
  143. Ogle NR, Akkerman SR. Guidance for the discontinuation or switching of antidepressant therapies in adults. J Pharm Pract. 2013;26(4):389-396. doi:10.1177/0897190012467210 [PubMed 23459282]
  144. Ortega E. Postherpetic neuralgia. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed June 22, 2022.
  145. Pacher P, Kecskemeti V. Cardiovascular side effects of new antidepressants and antipsychotics: new drugs, old concerns? Curr Pharm Des. 2004;10(20):2463-2475. doi:10.2174/1381612043383872 [PubMed 15320756]
  146. Pamelor (nortriptyline) capsules [prescribing information]. Hazelwood, MO: Mallinckrodt Inc; April 2019.
  147. Papakostas GI, Perlis RH, Scalia MJ, Petersen TJ, Fava M. A meta-analysis of early sustained response rates between antidepressants and placebo for the treatment of major depressive disorder. J Clin Psychopharmacol. 2006;26(1):56-60. doi:10.1097/01.jcp.0000195042.62724.76 [PubMed 16415707]
  148. Pass SE, Simpson RW. Discontinuation and Reinstitution of Medications During the Perioperative Period. Am J Health Syst Pharm. 2004;61(9):899-912. [PubMed 15156966]
  149. Patterson JF. Psychosis after discontinuation of nortriptyline. J Clin Psychopharmacol. 1984;4(2):117-118. [PubMed 6707238]
  150. Perroud N, Uher R, Marusic A, et al. Suicidal ideation during treatment of depression with escitalopram and nortriptyline in genome-based therapeutic drugs for depression (GENDEP): a clinical trial. BMC Med. 2009;7:60. doi:10.1186/1741-7015-7-60 [PubMed 19832967]
  151. Peterson SJB, Weisman SJ. Pediatric pain management. In: Kliegman RM, St Geme JW, Blum NJ, et al, eds. Nelson Textbook of Pediatrics. 22nd ed. Elsevier; 2025:chap 93.
  152. Pettengill CA, Reisner-Keller L. The use of tricyclic antidepressants for the control of chronic orofacial pain. Cranio. 1997;15(1):53-56. doi:10.1080/08869634.1997.11745992 [PubMed 9586488]
  153. Pliszka S and AACAP Work Group on Quality Issues. Practice Parameter for the Assessment and Treatment of Children and Adolescents With Attention-Deficit/Hyperactivity Disorder. J Am Acad Child Adolesc Psychiatry. 2007;46(7):894-921. [PubMed 17581453]
  154. Pollock BG, Mulsant BH, Nebes R, et al. Serum anticholinergicity in elderly depressed patients treated with paroxetine or nortriptyline. Am J Psychiatry. 1998;155(8):1110-1112. doi:10.1176/ajp.155.8.1110 [PubMed 9699704]
  155. Pop-Busui R, Boulton AJM, Feldman EL, et al. Diabetic neuropathy: A position statement by the American Diabetes Association. Diabetes Care. 2017;40(1):136-154. [PubMed 27999003]
  156. Posternak MA, Zimmerman M. Is there a delay in the antidepressant effect? A meta-analysis. J Clin Psychiatry. 2005;66(2):148-158. doi:10.4088/jcp.v66n0201 [PubMed 15704999]
  157. Preskorn SH, Jerkovich GS. Central nervous system toxicity of tricyclic antidepressants: phenomenology, course, risk factors, and role of therapeutic drug monitoring. J Clin Psychopharmacol. 1990;10(2):88-95. doi:10.1097/00004714-199004000-00003 [PubMed 2140373]
  158. Price R, Smith D, Franklin G, et al. Oral and topical treatment of painful diabetic polyneuropathy: practice guideline update summary: report of the AAN Guideline Subcommittee. Neurology. 2022;98(1):31-43. doi:10.1212/WNL.0000000000013038 [PubMed 34965987]
  159. Prince JB, Wilens TE, Biederman J, et al. A Controlled Study of Nortriptyline in Children and Adolescents With Attention Deficit Hyperactivity Disorder. J Child Adolesc Psychopharmacol. 2000;10(3):193-204. [PubMed 11052409]
  160. Pringsheim T, Davenport W, Mackie G, et al; Canadian Headache Society Prophylactic Guidelines Development Group. Canadian Headache Society guideline for migraine prophylaxis. Can J Neurol Sci. 2012;39(2)(suppl 2):S1-S59. [PubMed 22683887]
  161. Prochazka AV, Kick S, Steinbrunn C, Miyoshi T, Fryer GE. A randomized trial of nortriptyline combined with transdermal nicotine for smoking cessation. Arch Intern Med. 2004;164(20):2229-2233. doi:10.1001/archinte.164.20.2229 [PubMed 15534159]
  162. Prochazka AV, Weaver MJ, Keller RT, Fryer GE, Licari PA, Lofaso D. A randomized trial of nortriptyline for smoking cessation. Arch Intern Med. 1998;158(18):2035-2039. doi:10.1001/archinte.158.18.2035 [PubMed 9778204]
  163. Rabenda V, Nicolet D, Beaudart C, Bruyère O, Reginster JY. Relationship between use of antidepressants and risk of fractures: a meta-analysis. Osteoporos Int. 2013;24(1):121-137. doi:10.1007/s00198-012-2015-9 [PubMed 22638709]
  164. Raja SN, Haythornthwaite JA, Pappagallo M, et al. Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology. 2002;59(7):1015-1021. [PubMed 12370455]
  165. Rasmussen VF, Lundberg V, Jespersen TW, Hasle H. Extreme doses of intravenous methadone for severe pain in two children with cancer. Pediatr Blood Cancer. 2015;62(6):1087-1090. doi:10.1002/pbc.25392 [PubMed 25641929]
  166. Ray WA, Meredith S, Thapa PB, Hall K, Murray KT. Cyclic antidepressants and the risk of sudden cardiac death. Clin Pharmacol Ther. 2004;75(3):234-241. doi:10.1016/j.clpt.2003.09.019 [PubMed 15001975]
  167. Reeves RR, Brister JC. Serious suicide attempt with duloxetine treatment. South Med J. 2008;101(7):769. doi:10.1097/SMJ.0b013e318177872f [PubMed 19209119]
  168. Refer to manufacturer's labeling.
  169. Richa S, Yazbek JC. Ocular adverse effects of common psychotropic agents: a review. CNS Drugs. 2010;24(6):501-526. doi:10.2165/11533180-000000000-00000 [PubMed 20443647]
  170. Richards JB, Papaioannou A, Adachi JD, et al; Canadian Multicentre Osteoporosis Study Research Group. Effect of selective serotonin reuptake inhibitors on the risk of fracture. Arch Intern Med. 2007;167(2):188-194. doi:10.1001/archinte.167.2.188 [PubMed 17242321]
  171. Riedel W, van Praag HM. Avoiding and managing anticholinergic effects of antidepressants. CNS Drugs. 1995;3(4):245-259.
  172. Riediger C, Schuster T, Barlinn K, Maier S, Weitz J, Siepmann T. Adverse effects of antidepressants for chronic pain: A systematic review and meta-analysis. Front Neurol. 2017;8:307. doi:10.3389/fneur.2017.00307 [PubMed 28769859]
  173. Rizzoli R, Cooper C, Reginster JY, et al. Antidepressant medications and osteoporosis. Bone. 2012;51(3):606-613. doi:10.1016/j.bone.2012.05.018 [PubMed 22659406]
  174. Rollman BL, Block MR, Schulberg HC. Symptoms of major depression and tricyclic side effects in primary care patients. J Gen Intern Med. 1997;12(5):284-291. doi:10.1046/j.1525-1497.1997.012005284.x [PubMed 9159697]
  175. Roos JC. Cardiac effects of antidepressant drugs. A comparison of the tricyclic antidepressants and fluvoxamine. Br J Clin Pharmacol. 1983;15 Suppl 3(Suppl 3):439S-445S. doi:10.1111/j.1365-2125.1983.tb02135.x [PubMed 6407505]
  176. Roose SP, Glassman AH, Siris SG, Walsh BT, Bruno RL, Wright LB. Comparison of imipramine- and nortriptyline-induced orthostatic hypotension: a meaningful difference. J Clin Psychopharmacol. 1981;1(5):316-319. doi:10.1097/00004714-198109000-00008 [PubMed 6277997]
  177. Rubin EH, Biggs JT, Preskorn SH. Nortriptyline pharmacokinetics and plasma levels: implications for clinical practice. J Clin Psychiatry. 1985;46(10):418-424. [PubMed 3900052]
  178. Ruxton K, Woodman RJ, Mangoni AA. Drugs with anticholinergic effects and cognitive impairment, falls and all-cause mortality in older adults: A systematic review and meta-analysis. Br J Clin Pharmacol. 2015;80(2):209-220. Erratum in: Br J Clin Pharmacol. 2015;80(4):921-6. doi:10.1111/bcp.12617 [PubMed 25735839]
  179. Sabah KMN, Chowdhury AW, Islam MS, Saha BP, Kabir SR, Kawser S. Amitriptyline-induced ventricular tachycardia: a case report. BMC Res Notes. 2017;10(1):286. doi:10.1186/s13104-017-2615-8 [PubMed 28709467]
  180. Schatzberg AF, Blier P, Delgado PL, et al. Antidepressant discontinuation syndrome: consensus panel recommendations for clinical management and additional research. J Clin Psychiatry. 2006;67(Suppl 4):27-30. [PubMed 16683860]
  181. Schoretsanitis G, Spigset O, Stingl JC, Deligiannidis KM, Paulzen M, Westin AA. The impact of pregnancy on the pharmacokinetics of antidepressants: a systematic critical review and meta-analysis. Expert Opin Drug Metab Toxicol. 2020;16(5):431-440. doi:10.1080/17425255.2020.1750598 [PubMed 32238008]
  182. Schoretsanitis G, Westin AA, Stingl JC, Deligiannidis KM, Paulzen M, Spigset O. Antidepressant transfer into amniotic fluid, umbilical cord blood & breast milk: a systematic review & combined analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2021;107:110228. doi:10.1016/j.pnpbp.2020.110228 [PubMed 33358964]
  183. Shelton RC. Steps following attainment of remission: discontinuation of antidepressant therapy. Prim Care Companion J Clin Psychiatry. 2001;3(4):168-174. doi:10.4088/pcc.v03n0404 [PubMed 15014601]
  184. Sherafat A, Sahebnasagh A, Rahmany R, Mohammadi F, Saghafi F. The preventive effect of the combination of atorvastatin and nortriptyline in migraine-type headache: a randomized, triple-blind, placebo-controlled trial. Neurol Res. 2022;44(4):311-317. doi:10.1080/01616412.2021.1981105 [PubMed 35037597]
  185. Spencer T, Biederman J, Wilens T, Harding M, O'Donnell D, Griffin S. Pharmacotherapy of attention-deficit hyperactivity disorder across the life cycle. J Am Acad Child Adolesc Psychiatry. 1996;35(4):409-432. [PubMed 8919704]
  186. Sriraman NK, Melvin K, Meltzer-Brody S. ABM Clinical Protocol #18: use of antidepressants in breastfeeding mothers. Breastfeed Med. 2015;10(6):290-299. [PubMed 26204124]
  187. Steiner TJ, Jensen R, Katsarava Z, et al. Aids to management of headache disorders in primary care (2nd edition): on behalf of the European Headache Federation and Lifting The Burden: the Global Campaign against Headache. J Headache Pain. 2019;20(1):57. doi:10.1186/s10194-018-0899-2 [PubMed 31113373]
  188. Sun-Edelstein C, Tepper SJ, Shapiro RE. Drug-induced serotonin syndrome: a review. Expert Opin Drug Saf. 2008;7(5):587-596. doi:10.1517/14740338.7.5.587 [PubMed 18759711]
  189. Sweetman S, ed. Martindale: The Complete Drug Reference. 37th ed. New York: NY: Pharmaceutical Press; 2012.
  190. Szanto K, Mulsant BH, Houck PR, et al. Emergence, persistence, and resolution of suicidal ideation during treatment of depression in old age. J Affect Disord. 2007;98(1-2):153-161. doi:10.1016/j.jad.2006.07.015 [PubMed 16934334]
  191. Szegedi A, Jansen WT, van Willigenburg AP, van der Meulen E, Stassen HH, Thase ME. Early improvement in the first 2 weeks as a predictor of treatment outcome in patients with major depressive disorder: a meta-analysis including 6562 patients. J Clin Psychiatry. 2009;70(3):344-353. doi:10.4088/jcp.07m03780 [PubMed 19254516]
  192. Talley NJ, Locke GR, Saito YA, et al. Effect of amitriptyline and escitalopram on functional dyspepsia: a multicenter, randomized controlled study. Gastroenterology. 2015;149(2):340-9.e2. doi:10.1053/j.gastro.2015.04.020 [PubMed 25921377]
  193. Tauben D, Stacey BR. Pharmacologic management of chronic non-cancer pain in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed June 22, 2022.
  194. Taylor FR. Tension-type headache in adults: preventive treatment. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed August 3, 2022.
  195. Taylor JJ, Wilson JW, Estes LL. Linezolid and serotonergic drug interactions: a retrospective survey. Clin Infect Dis. 2006;43(2):180-187. doi:10.1086/504809 [PubMed 16779744]
  196. Tisdale JE, Chung MK, Campbell KB, et al; American Heart Association Clinical Pharmacology Committee of the Council on Clinical Cardiology and Council on Cardiovascular and Stroke Nursing. Drug-induced arrhythmias: A scientific statement from the American Heart Association. Circulation. 2020;142(15):e214-e233. doi:10.1161/CIR.0000000000000905 [PubMed 32929996]
  197. US Department of Health and Human Services (HHS). Smoking cessation. A report of the Surgeon General. https://www.hhs.gov/sites/default/files/2020-cessation-sgr-full-report.pdf. Updated 2020. Accessed June 15, 2022.
  198. US Department of Veterans Affairs/Department of Defense (VA/DoD). VA/DoD clinical practice guideline for the management of major depressive disorder. https://www.healthquality.va.gov/guidelines/MH/mdd/VADoDMDDCPGFinal508.pdf. Updated February 2022. Accessed June 15, 2022.
  199. van Eijk ME, Avorn J, Porsius AJ, de Boer A. Reducing prescribing of highly anticholinergic antidepressants for elderly people: randomised trial of group versus individual academic detailing. BMJ. 2001;322(7287):654-657. doi:10.1136/bmj.322.7287.654 [PubMed 11250852]
  200. van Geffen EC, Hugtenburg JG, Heerdink ER, van Hulten RP, Egberts AC. Discontinuation symptoms in users of selective serotonin reuptake inhibitors in clinical practice: tapering versus abrupt discontinuation. Eur J Clin Pharmacol. 2005;61(4):303-307. doi:10.1007/s00228-005-0921-x [PubMed 15906018]
  201. Venkatesan T, Levinthal DJ, Tarbell SE, et al. Guidelines on management of cyclic vomiting syndrome in adults by the American Neurogastroenterology and Motility Society and the Cyclic Vomiting Syndrome Association. Neurogastroenterol Motil. 2019;31(suppl 2):e13604. doi:10.1111/nmo.13604 [PubMed 31241819]
  202. Vestergaard P, Rejnmark L, Mosekilde L. Selective serotonin reuptake inhibitors and other antidepressants and risk of fracture. Calcif Tissue Int. 2008;82(2):92-101. doi:10.1007/s00223-007-9099-9 [PubMed 18219438]
  203. Wadhwa R, Kumar M, Talegaonkar S, Vohora D. Serotonin reuptake inhibitors and bone health: A review of clinical studies and plausible mechanisms. Osteoporos Sarcopenia. 2017;3(2):75-81. doi:10.1016/j.afos.2017.05.002 [PubMed 30775508]
  204. Wagner KD. Pharmacotherapy for Major Depression in Children and Adolescents. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29(5):819-826. [PubMed 15908090]
  205. Wald A. Treatment of irritable bowel syndrome in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed August 26, 2022.
  206. Walker EA, Roy-Byrne PP, Katon WJ, Jemelka R. An open trial of nortriptyline in women with chronic pelvic pain. Int J Psychiatry Med. 1991;21(3):245-252. doi:10.2190/EXRP-J206-CBWT-UTFK [PubMed 1955276]
  207. Waring WS. Clinical use of antidepressant therapy and associated cardiovascular risk. Drug Healthc Patient Saf. 2012;4:93-101. doi:10.2147/DHPS.S28804 [PubMed 22936860]
  208. Warner CH, Bobo W, Warner C, Reid S, Rachal J. Antidepressant discontinuation syndrome. Am Fam Physician. 2006;74(3):449-456. [PubMed 16913164]
  209. Watson CP, Vernich L, Chipman M, Reed K. Nortriptyline versus amitriptyline in postherpetic neuralgia: a randomized trial. Neurology. 1998;51(4):1166-1171. [PubMed 9781549]
  210. Weissman AM, Levy BT, Hartz AJ, et al. Pooled analysis of antidepressant levels in lactating mothers, breast milk, and nursing infants. Am J Psychiatry. 2004;161(6):1066-1078. [PubMed 15169695]
  211. Wilens TE, Biederman J, Baldessarini RJ, et al. Cardiovascular effects of therapeutic doses of tricyclic antidepressants in children and adolescents. J Am Acad Child Adolesc Psychiatry. 1996;35(11):1491-1501. doi:10.1097/00004583-199611000-00018. [PubMed 8936916]
  212. Wilens TE, Biederman J, Geist DE, Steingard R, Spencer T. Nortriptyline in the treatment of ADHD: a chart review of 58 cases. J Am Acad Child Adolesc Psychiatry. 1993;32(2):343-349. [PubMed 8444763]
  213. Wisner KL, Hanusa BH, Perel JM, et al. Postpartum depression: a randomized trial of sertraline versus nortriptyline. J Clin Psychopharmacol. 2006;26(4):353-360. doi:10.1097/01.jcp.0000227706.56870.dd [PubMed 16855451]
  214. Wolraich ML, Hagan JF Jr, Allan C, et al. Clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics. 2019;144(4):e20192528. doi:10.1542/peds.2019-2528 [PubMed 31570648]
  215. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2):97-170. doi: 10.1111/bdi.12609. [PubMed 29536616]
  216. Yonkers KA, Blackwell KA, Glover J, Forray A. Antidepressant use in pregnant and postpartum women. Annu Rev Clin Psychol. 2014;10:369-392. doi:10.1146/annurev-clinpsy-032813-153626 [PubMed 24313569]
  217. Yue M, Kus L, Katta S, et al. Pharmacokinetics of Antidepressants in Pregnancy. J Clin Pharmacol. 2023;63(suppl 1):S137-S158. doi:10.1002/jcph.2282 [PubMed 37317494]
  218. Zimmermann-Viehoff F, Kuehl LK, Danker-Hopfe H, Whooley MA, Otte C. Antidepressants, autonomic function and mortality in patients with coronary heart disease: data from the Heart and Soul Study. Psychol Med. 2014;44(14):2975-2984. doi:10.1017/S003329171400066X [PubMed 25065442]
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