Professional Information

Antidepressants, Tricyclic (Systemic)

This monograph includes information on the following:

1) Amitriptyline
2) Amoxapine
3) Clomipramine
4) Desipramine
5) Doxepin
6) Imipramine
7) Nortriptyline
8) Protriptyline
9) Trimipramine

VA CLASSIFICATION
Amitriptyline
Primary: CN601
Secondary: GU900; CN103; GA309; CN900

Amoxapine
Primary: CN601

Clomipramine
Primary: CN601
Secondary: CN900; CN103

Desipramine
Primary: CN601
Secondary: CN103; CN900

Doxepin
Primary: CN601
Secondary: CN900; DE890; CN103 ; GA309

Imipramine
Primary: CN601
Secondary: GU900; CN900; CN103

Nortriptyline
Primary: CN601
Secondary: CN103; CN900

Protriptyline
Primary: CN601
Secondary: CN900

Trimipramine
Primary: CN601
Secondary: GA309; CN103

Commonly used brand name(s): Anafranil³; Apo-Amitriptyline¹; Apo-Imipramine⁶; Apo-Trimip⁹; Asendin²; Aventyl⁷; Elavil¹; Endep¹; Impril⁶; Levate¹; Norfranil⁶; Norpramin⁴; Novo-Doxepin⁵; Novo-Tripramine⁹; Novopramine⁶; Novotriptyn¹; Pamelor⁷; Pertofrane⁴; Rhotrimine⁹; Sinequan⁵; Surmontil⁹; Tipramine⁶; Tofranil⁶; Tofranil-PM⁶; Triadapin⁵; Triptil⁸; Vivactil⁸.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Category:

Note: All of the tricyclic antidepressants have similar pharmacologic actions; however, clinical uses among specific agents may vary because of actual pharmacokinetic differences, availability of specific testing, differences in side effects ^{87}, and/or availability of clinical-use data.

Antidepressant—Amitriptyline; Amoxapine; Clomipramine; Desipramine; Doxepin; Imipramine; Nortriptyline; Protriptyline; Trimipramine;

Antienuretic—Amitriptyline; Imipramine Hydrochloride;

Antiobsessive-compulsive agent—Clomipramine;

Antipanic agent—Clomipramine; Desipramine^{88}; Doxepin; Imipramine^{153}; Nortriptyline^{150}^{152}^{159};

Antineuralgic—Amitriptyline; Clomipramine^{150}^{160}; Desipramine; Doxepin; Imipramine; Nortriptyline; Trimipramine^{151};

Antiulcer agent—Amitriptyline; Doxepin; Trimipramine;

Antinarcolepsy adjunct—Imipramine; Protriptyline^{150};

Anticataplectic—Clomipramine; Desipramine; Imipramine; Protriptyline;

Antibulimic—Amitriptyline; Clomipramine^{150}; Desipramine; Imipramine;

Antipruritic—Doxepin;

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Depression, mental (treatment)—Amitriptyline, amoxapine, [clomipramine] , desipramine, doxepin, imipramine, nortriptyline, protriptyline, and trimipramine are indicated for the relief of symptoms of major depressive episodes ^{01}; bipolar disorder, depressed type ^{01}; dysthymia ^{89}; and atypical depressions. Some conditions associated with or accompanied by depression that are treated with tricyclic antidepressants include alcoholism, organic disease such as stroke or Parkinson's disease, and agitation or anxiety.

Enuresis (treatment adjunct)—Imipramine hydrochloride ^{39}, but not pamoate, and [amitriptyline^{118}] are indicated as aids in the temporary treatment of nocturnal enuresis in children 6 years of age or older, after possible organic causes have been excluded by appropriate tests.

Obsessive-compulsive disorder (treatment)—Clomipramine is used to relieve symptoms of obsessive-compulsive disorders, independent of concomitant depression ^{02} ^{42} ^{69} ^{112} ^{126}.

[Panic disorder (treatment)]¹ ^{04}^{13}^{189}—Tricyclic antidepressants, especially clomipramine, desipramine, doxepin, ^{88} imipramine, and nortriptyline ^{150} ^{152} ^{159} are used in conjunction with psychotherapy and behavior therapy to block the recurrence of panic attacks, with or without phobias. Imipramine's antipanic effect does not appear to be correlated with presence of depressive symptoms. ^{42}

[Pain, neurogenic (treatment)]¹—Tricyclic antidepressants, especially amitriptyline, clomipramine ^{150} ^{160}, desipramine, doxepin, imipramine, nortriptyline, and trimipramine ^{151} are used in patients with normal or depressed mood ^{40} ^{41} for the management of chronic, severe pain as in cancer; migraine and chronic, daily muscle-contraction headaches; rheumatic disorders; atypical facial pain; post-herpetic neuralgia; post-traumatic neuropathy ^{02}; and diabetic or other ^{02} peripheral neuropathy.

[Attention deficit hyperactivity disorder (treatment)]¹ ^{188}—Desipramine, imipramine, and protriptyline ^{60} are used to relieve the symptoms of attention deficit hyperactivity disorder in some children over 6 years of age and in young adults ^{103}. Tricyclic antidepressants may be more useful than stimulants when the patient has become withdrawn and depressed ^{36}.

[Headache (prophylaxis)]¹—Tricyclic antidepressants are used in the prophylaxis of vascular headache (including migraine) and mixed headache syndrome ^{142} ^{143} ^{144} ^{145} ^{146} ^{147} ^{148}.

[Ulcer, peptic (treatment)]¹—Although amitriptyline, doxepin, and trimipramine are effective in the treatment of peptic ulcer disease and in relieving nocturnal ulcer pain ^{43} ^{56}, their use has been largely supplanted by histamine H ₂-receptor antagonists, omeprazole, and sucralfate ^{176}.

[Narcolepsy/cataplexy syndrome (treatment)]¹or
[Narcolepsy/cataplexy syndrome (treatment adjunct)]¹—Tricyclic antidepressants, especially clomipramine, desipramine, imipramine, and protriptyline, are used to treat cataplexy associated with narcolepsy, with little or no effect on narcoleptic sleep attacks. Imipramine may be used in combination with amphetamines or methylphenidate when a patient requires treatment for both cataplexy and sleep attacks. ^{37} Patients with sleep disorders such as hypersomnia or impaired morning arousal may benefit by the use of protriptyline ^{84}.

[Bulimia nervosa^{88} (treatment)]¹ ^{189}—Amitriptyline, clomipramine ^{150}, desipramine, and imipramine have been shown to be effective in controlling the binge eating and subsequent purging of bulimia nervosa ^{44} ^{47}.

[Cocaine withdrawal (treatment)]¹ ^{189}—Desipramine and imipramine are used to reduce craving and/or prevent depression upon withdrawal of cocaine ^{59} ^{80}.

[Urinary incontinence (treatment)]¹—Imipramine is used for the treatment of stress and urge incontinence ^{172} ^{173} ^{174} ^{175} ^{176} ^{178} ^{179} ^{187}.

[Pruritus (treatment)]¹—Doxepin is used in treatment of pruritus in idiopathic cold urticaria.

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Table 1. Pharmacology/Pharmacokinetics

Drug	Anticholinergic Effects ^*	Sedation ^*	Orthostatic Hypotension ^*	Active Metabolites	Protein Binding (%)	Volume of Distribution (L/Kg)	Half-life (hours)	Therapeutic Plasma Concentration (ng/mL) ^†
Amitriptyline	High ^{45} ^{133} ^{139}	High ^{45} ^{133} ^{139}	Moderate to high ^{45} ^{133} ^{139}	Nortriptyline 10-Hydroxyamitriptyline ^{33} ^{150}	95 ^{33} ^{45}	12–18 ^{33} ^{45}	10–26 ^{33} ^{45}
Amoxapine	Moderate ^{45}	Low to moderate ^{45}	Low ^{45}	7- and 8-Hydroxyamoxapine ^{119}	92 ^{119}	N.A. ^‡	8–30 ^{45}
Clomipramine	High ^{150} ^{151} ^{152}	Moderate ^{150} ^{152}	Moderate	Desmethylclomipramine ^{69} ^{112} ^{126}	96–97 ^{69} ^{112} ^{126}	12 ^{182} ^{183}	21–31 ^{69} ^{101}
Desipramine	Low ^{133} ^{139}	Low ^{45} ^{57} ^{133} ^{139}	Moderate ^{45} ^{133}	2-Hydroxydesipramine ^{154}	90–92 ^{45} ^{154}	17–42 ^{33} ^{45}	12–27 ^{33} ^{45} ^{57}	125–300 ^{150} ^{153} ^{164} ^{176} ^{184} ^{186}
Doxepin	High ^{142} ^{151}	High ^{45} ^{133} ^{139}	High ^{139}	Desmethyldoxepin ^{113}	N.A. ^‡	12–28 ^{33} ^{45}	11–23 ^{33} ^{45}
Imipramine	Moderate ^{133} ^{139}	Moderate ^{45} ^{57} ^{133} ^{139}	High ^{45} ^{133}	Desipramine 2-Hydroxydesipramine ^{33} ^{150}	89–95 ^{33} ^{45}	15–31 ^{33} ^{45}	11–25 ^{33} ^{45}	150–300 ^{149} ^{176} ^{184} ^{186} ^§
Nortriptyline	Low ^{139}	Moderate ^{45} ^{133} ^{139}	Low ^{45} ^{108} ^{133} ^{139}	10-Hydroxynortriptyline ^{33} ^{115}	92 ^{33} ^{45}	14–22 ^{33} ^{45}	18–44 ^{33} ^{45} ^{57}	50–150 ^{33} ^{45} ^{115} ^{117} ^{149} ^{186} ^**
Protriptyline	Moderate ^{45} ^{139}	Very low ^{45} ^{139}	Low ^{45} ^{139}	N.A. ^‡	92 ^{33} ^{45}	22 ^{33}	67–89 ^{33} ^{45}
Trimipramine	High ^{45} ^{139}	High ^{45} ^{57} ^{139}	Moderate ^{45} ^{139}	N.A. ^‡	N.A. ^‡	N.A. ^‡	9–11 ^{64}

^* Relative effects among tricyclic antidepressants only.
^† Although various values have been reported, there is little consensus about therapeutic plasma concentrations, except for desipramine, imipramine, and nortriptyline ^{151} ^{155} ^{156} ^{157}. Steady-state plasma levels exhibit marked interindividual variations due to genetic factors (e.g., hepatic metabolism) and physiochemical properties of the medication (e.g., lipid solubility) ^{149}.
^‡ Not available.
^§ Includes metabolites.
^** Denotes therapeutic window, outside of which effects are lessened ^{33} ^{149} ^{150}.

Physicochemical characteristics:
Molecular weight—
    Amitriptyline hydrochloride: 313.87
    Amoxapine: 313.79
    Clomipramine hydrochloride: 351.32
    Desipramine hydrochloride: 302.85
    Doxepin hydrochloride: 315.84
    Imipramine hydrochloride: 316.87
    Imipramine pamoate: 949.2 ^{61}
    Nortriptyline hydrochloride: 299.84
    Protriptyline hydrochloride: 299.84
    Trimipramine maleate: 410.51

pKa—
    Amitriptyline: 9.4
    Amoxapine: 7.6
    Clomipramine: 9.5 ^{126}
    Desipramine: 1.5 and 10.2
    Doxepin: 9.0
    Imipramine: 9.5
    Nortriptyline: 9.7
    Trimipramine: 8.0

Mechanism of action/Effect:

Antidepressant:

Although the exact mechanism of action in the treatment of depression is unclear, tricyclic antidepressants have been thought to increase the synaptic concentration of norepinephrine (levarterenol; NE) and/or serotonin (5-hydroxytryptamine; 5-HT) in the central nervous system (CNS) ^{57}. One theory suggests that these neurotransmitters are increased through inhibition of their reuptake by the presynaptic neuronal membrane ^{57}.

Amoxapine ^{119}, desipramine ^{120}, trimipramine, nortriptyline, ^{48} and probably protriptyline mainly inhibit the reuptake of norepinephrine. Amitriptyline and clomipramine appear to be more potent than other tricyclics in blocking serotonin, although, through their metabolites, they become powerful inhibitors of norepinephrine reuptake also ^{48} ^{49}. Clomipramine's effectiveness in the treatment of obsessive-compulsive disorder may be related to the inhibition of serotonin reuptake ^{104} ^{105}. Imipramine inhibits reuptake of norepinephrine and serotonin equally ^{48}. Doxepin is a moderate inhibitor of norepinephrine and a weak inhibitor of serotonin ^{99}.

Recent research has shown that after long-term treatment with antidepressants, changes in postsynaptic ^{48} beta-adrenergic receptor sensitivity and increased responsiveness of the adrenergic and serotonergic systems to physiologic and environmental stimuli ^{88} contribute to the mechanism of action. Antidepressants may produce a downregulation (desensitization) of alpha ₂- or beta-adrenergic and serotonin receptors, equilibrating the noradrenergic system, and thus correcting the dysregulated monoamine output of depressed patients ^{45}. Receptor changes resulting from chronic administration of tricyclic antidepressants appear to correlate better with antidepressant action than does the synaptic reuptake blockade of neurotransmitters, and may also account for the delay of 2 to 4 weeks in therapeutic response ^{02} ^{21} ^{22}.

Amoxapine, as a metabolite of the neuroleptic, loxapine, also has a potent postsynaptic dopamine-blocking effect. This may account for the extrapyramidal side effects and increases in serum prolactin concentrations seen with amoxapine. Amoxapine is metabolized to 7-hydroxyamoxapine, also a potent dopamine-blocking agent ^{65}.

Antienuretic:

The exact antienuretic action of imipramine hydrochloride has not been established. It is thought to be associated with the anticholinergic effects of imipramine ^{64}.

Antiobsessional agent:

The exact antiobsessional action of clomipramine has not been established. It is thought to be associated with clomipramine's inhibition of serotonin reuptake ^{126} and compensatory down regulation of serotonin receptor subtypes ^{150}.

Antianxiety agent:

In panic disorders, studies suggest an impaired function of the autonomic nervous system that causes an excessive release of norepinephrine from the locus ceruleus. Tricyclic antidepressants are thought to decrease the firing rate of the locus ceruleus by regulating the alpha ₂- and beta-adrenergic receptor functions and norepinephrine turnover. ^{55}

Antineuralgic:

The exact mechanism by which tricyclic antidepressants relieve chronic pain is also unknown. Some studies support the theory that pain relief results when depression is relieved. However, other studies have found that pain may be ameliorated without a significant change in depression. Analgesic activity may be effected by the changing concentrations of central monoamines, especially serotonin, and by the direct or indirect effect of tricyclic antidepressants on the endogenous opioid systems. ^{40}

Antiulcer agent:

In peptic ulcer disease, tricyclic antidepressants are effective in relieving pain and aid in complete healing because of their histamine ₂-receptor blocking property on the parietal cells, and their sedative and anticholinergic effects ^{43} ^{56}.

Antibulimic:

In bulimia nervosa, the mechanism of action is unclear, although it may be similar to that in depression. Evidence shows there is a distinct antibulimic effect in patients without depression and in depressed patients whose bulimia was relieved without a concomitant relief of depression. ^{47}

Urinary incontinence:

The exact mechanism by which imipramine enhances urinary continence has not been established but may include anticholinergic activity, resulting in increased bladder capacity; direct beta-adrenergic stimulation; alpha-adrenergic agonist activity, resulting in increased sphincter tone ^{173} ^{187}; and central blockade of serotonin uptake ^{180}.

Other actions/effects:

Tricyclic antidepressants also produce prominent peripheral and central anticholinergic effects ^{64} ^{69} ^{113} due to their potent and high binding affinity for muscarinic receptors; sedative effects due to strong binding affinity for histamine H ₁-receptors (although the central actions of histamine are poorly understood, increased cholinoceptive activity in the brain has been associated with clinical depression); and orthostatic hypotension due to alpha blockade ^{108}. In addition, tricyclic antidepressants are Class 1A antiarrhythmic agents ^{168} which, like quinidine, moderately slow ventricular conduction in therapeutic doses ^{167} ^{168}, and in overdose may cause severe conduction block and occasional ventricular arrhythmia ^{167}.

Absorption:

Rapidly and well absorbed after oral administration ^{64} ^{69} ^{119} ^{120} ^{124} ^{126}.

Protein binding:

Very highly protein bound (90% or more) in plasma and tissues ^{64} ^{126}.

Biotransformation:

Exclusively hepatic ^{120} ^{124}, with first-pass effect ^{64} ^{126}.

Onset of action:

Antidepressant—2 to 3 weeks ^{39} ^{121} ^{122} ^{123} ^{150} ^{153} ^{156}.

Elimination:
    As metabolites, primarily renal ^{64} ^{69} ^{119} ^{120} ^{124} ^{126}, over several days; poorly dialyzable because of high protein binding.

Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to one tricyclic antidepressant may be sensitive to other tricyclic antidepressants ^{115} ^{116} ^{117} ^{120} ^{121} ^{122} ^{123}, and possibly to carbamazepine ^{161}, maprotiline, and trazodone, also.

Carcinogenicity/Mutagenicity

Amitriptyline—In one study with rats, no evidence of increase in incidence of any tumor was found. However, amitriptyline has not been adequately studied in animals to permit an evaluation of its carcinogenic potential. ^{86} No evidence of mutagenicity was found in rats tested with the Ames salmonella test.

Amoxapine—Pancreatic islet cell hyperplasia occurred in rats, with slightly increased incidence at doses 5 to 10 times the human dose ^{119}.

Pregnancy/Reproduction

Pregnancy—

For amitriptyline

Adequate and well-controlled studies in pregnant women have not been done.

Animal studies have shown amitriptyline to cause teratogenic effects when used in doses many times the human dose.

FDA Pregnancy Category C ^{86}.

For amoxapine

Adequate and well-controlled studies in pregnant women have not been done.

Animal studies have shown amoxapine to cause embryotoxic effects in doses approximating the human dose and fetotoxic effects such as intrauterine death, stillbirth, decreased birth weight, and decreased postnatal (0 to 4 days) survival ^{68} at doses many times the human dose.

FDA Pregnancy Category C ^{119}.

For clomipramine ^{69}, desipramine ^{26}, and nortriptyline ^{24}

Adequate and well-controlled studies in pregnant women have not been done.

Animal reproduction studies have been inconclusive.

FDA Pregnancy Category C ^{112}.

For doxepin

Adequate and well-controlled studies in pregnant women have not been done.

Animal studies have shown no evidence of teratogenic effects at doses up to 25 mg per kg of body weight (mg/kg) per day for 8 to 9 months and no changes in litter size, number of live births, or lactation. However, a decreased rate of conception was observed when male rats were given 25 mg/kg per day for prolonged periods. ^{23}

For imipramine

Adequate and well-controlled studies in pregnant women have not been done ^{39} ^{123}. However, there have been clinical reports of congenital malformations associated with the use of imipramine ^{39} ^{123}.

Animal reproduction studies have been inconclusive ^{26} ^{127}.

For protriptyline

Adequate and well-controlled studies in pregnant women have not been done.

Animal reproduction studies have shown that protriptyline causes no apparent adverse effects at doses 10 times greater than recommended human doses ^{25} ^{124}.

For trimipramine

Adequate and well-controlled studies in pregnant women have not been done.

Animal studies have shown trimipramine to cause embryotoxicity and major anomalies at 20 times the human dose.

FDA Pregnancy Category C ^{116}.

Delivery—

For all tricyclic antidepressants: There have been reports of cardiac problems ^{02}, irritability ^{158}, respiratory distress ^{122} ^{158}, muscle spasms ^{02}, seizures ^{112} ^{158}, and urinary retention ^{158} in infants whose mothers received tricyclic antidepressants immediately prior to delivery.

Breast-feeding

Tricyclic antidepressants have been found in small amounts in breast milk ^{39} ^{64} ^{69} ^{112} ^{119} ^{123} in an approximate milk to plasma ratio of 0.4:1.5 ^{45}. Doxepin has been reported to cause sedation and respiratory depression in the nursing infant ^{50} ^{70}.

Pediatrics

Although tricyclic antidepressants are generally not recommended for depression in children under 12 years of age, some, especially amitriptyline, desipramine, imipramine, and nortriptyline ^{108}, are used in children over the age of 6 years for recognized major depressive illness ^{66}. However, the effectiveness of tricyclic antidepressants in the treatment of depression in children and adolescents has not been definitively established ^{155} ^{176} ^{181}. Amitriptyline ^{118} and imipramine ^{39} are also used for treatment of enuresis in children 6 years of age or older. Clomipramine is used for the treatment of obsessive-compulsive disorder in children 10 years of age or older ^{112}. Imipramine, desipramine, and protriptyline are being used in the treatment of attention deficit hyperactivity disorder in children over 6 years of age and adolescents ^{66}. However, deaths have been reported in children treated with desipramine for hyperactivity ^{114} ^{120} ^{162}.

Children are more sensitive than adults to acute overdosage, which should be considered serious and potentially fatal ^{39} ^{116} ^{123}. Increasing the dose in children increases the risk of adverse effects, such as alterations in electrocardiogram (ECG) patterns, nervousness, sleep disorders, tiredness, hypertension in some children ^{02}, or mild gastrointestinal problems, without necessarily enhancing the therapeutic effect. Adolescent patients may require reduced dosage because they are also prone to exhibit increased dose sensitivity ^{116} ^{117}.

Geriatrics

Elderly patients often require lower dosage and more gradual dose increases ^{39} ^{69} ^{113} ^{116} ^{117} ^{119} ^{120} to avoid toxicity, because of slower metabolic rates ^{120} and/or excretion and an increased ratio of fat to lean tissue. The elderly also exhibit increased sensitivity to anticholinergic effects, such as urinary retention (especially in older men with prostatic hypertrophy) ^{110}, anticholinergic delirium, and increased sedative and hypotensive effects. Increased anxiety may result from these adverse effects, possibly leading to unnecessary dose increases. If cardiovascular disease is present, the risk of conduction defects, arrhythmias, tachycardia, stroke, congestive heart failure, or myocardial infarction is increased. ^{113}

Dental

The peripheral anticholinergic effects of tricyclic antidepressants may decrease or inhibit salivary flow, especially in middle-aged or elderly patients, thus contributing to the development of caries, periodontal disease, oral candidiasis, and discomfort.

The blood dyscrasia–causing effects of tricyclic antidepressants, although rare, may be life-threatening ^{88}. The result may be an increased incidence of microbial infection, delayed healing, and gingival bleeding. If agranulocytosis, leukopenia, or thrombocytopenia occurs, dental work should be deferred until blood counts have returned to normal. Patient instruction in proper oral hygiene should include caution in use of regular toothbrushes, dental floss, and toothpicks. ^{27}

Extrapyramidal reactions that may be induced by amoxapine will result in increased motor activity of the head, face, and neck. Occlusal adjustments, bite registrations, and treatment for bruxism may be made less reliable. ^{91}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Although not all of the following interactions have been reported for every tricyclic antidepressant, the potential for their occurrence exists and should be considered.

» Alcohol^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{118}^{120}^{121}^{123}^{124}^{125} or
» CNS depression–producing medications, other^{39}^{69}^{112}^{113}^{118}^{119}^{120}^{121}^{123}^{124}^{125} (See Appendix II)    (concurrent use with tricyclic antidepressants may result in serious potentiation of CNS depression, respiratory depression, and hypotensive effects; caution is recommended, and dosage of one or both agents should be reduced ^{106})

    (in addition, tricyclics may increase the effects of alcohol, especially during first few days of tricyclic antidepressant treatment; in patients who use alcohol excessively, tricyclics may increase the danger inherent in any suicide attempt ^{115} ^{120})

Amantadine or
Anticholinergics or other medications with anticholinergic activity^{39}^{69}^{112}^{113}^{116}^{117}^{118}^{119}^{120}^{121}^{123}^{124}^{125} (See Appendix II ) or
Antidyskinetics or
Antihistamines    (concurrent use with tricyclic antidepressants may intensify anticholinergic effects, especially mental confusion, hallucinations, and nightmares, because of secondary anticholinergic activities of tricyclic antidepressants)

    (concurrent use may potentiate the CNS depressant effects of either antihistamines or tricyclic antidepressants)

    (concurrent use with tricyclic antidepressants may block detoxification of atropine and related compounds; patients should be advised to report occurrence of gastrointestinal problems promptly since paralytic ileus may occur with concurrent therapy)

Anticoagulants^{112}^{125} , coumarin- or indandione-derivative    (concurrent use with tricyclic antidepressants, especially amitriptyline or nortriptyline, may increase anticoagulant activity, possibly by inhibiting enzymatic metabolism of the anticoagulant)

Anticonvulsants^{125}    (tricyclic antidepressants may enhance CNS depression, lower the seizure threshold when taken in high doses, and decrease the effects of the anticonvulsant medication; dosage adjustment of the anticonvulsant may be necessary to control seizures; monitoring of serum concentrations of both medications may be necessary to detect possible interaction ^{04}; concurrent use of phenytoin with desipramine may lower serum concentrations of desipramine; dosage increases of desipramine above maximum recommended doses may be required to produce clinical improvement in depression ^{75})

» Antithyroid agents    (concurrent use with tricyclic antidepressants may increase the risk of agranulocytosis)

Barbiturates^{112}^{119}^{120} or
Carbamazepine^{88}    (plasma concentrations and therapeutic effects of tricyclic antidepressants may be decreased during concurrent use with barbiturates, especially phenobarbital, or carbamazepine because of increased metabolism resulting from induction of hepatic microsomal enzymes)

Bupropion^{163} or
Clozapine^{150}^{163} or
Cyclobenzaprine or
Haloperidol^{112}^{125} or
Loxapine^{163} or
Maprotiline^{163} or
Molindone^{163} or
» Phenothiazines^{120}^{125} or
Thioxanthenes^{163}    (the sedative and anticholinergic effects of either these medications or tricyclic antidepressants may be prolonged and intensified; these medications may increase the risk of seizures by lowering the seizure threshold and should be added or withdrawn with caution; psychotic depressions respond well to a combination of tricyclic antidepressant and antipsychotic agent, but both medications must be initially administered at lower ^{93} doses and are increased only as clinically indicated ^{52})

    (concurrent use of phenothiazines may increase serum concentrations of tricyclic antidepressants, especially desipramine and imipramine, due to inhibition of metabolism; conversely, tricyclics may inhibit phenothiazine metabolism ^{107}; also, the risk of neuroleptic malignant syndrome [NMS] may be increased ^{107})

» Cimetidine^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{119}^{120}^{121}^{122}^{123}^{124}^{125}    (cimetidine may inhibit tricyclic metabolism and increase plasma concentrations, leading to toxicity; lowering the dose of the tricyclic antidepressant by 20 to 30% may be necessary when cimetidine is given concurrently; patient should be closely observed for sedation, anticholinergic effects, and orthostatic hypotension ^{28})

» Clonidine^{39}^{112}^{123}^{125} or
» Guanadrel^{170} or
» Guanethidine^{39}^{112}^{113}^{115}^{117}^{118}^{120}^{121}^{123}^{124}^{125}    (concurrent use may decrease the hypotensive effects of these medications)

    (concurrent use of clonidine with tricyclic antidepressants may result in potentiation of CNS depressant effects)

Cocaine    (concurrent use with tricyclic antidepressants may increase the risk of cardiac arrhythmias; if use of cocaine is necessary in patients receiving tricyclics, it is recommended that the cocaine be administered with caution, in reduced dosage, and in conjunction with electrocardiographic monitoring ^{79})

Contraceptives, oral, estrogen-containing^{125} or
Estramustine or
Estrogens^{125}    (concurrent use of imipramine and possibly other tricyclic antidepressants by chronic long-term users of oral contraceptives or estrogens may increase the bioavailability of imipramine because of inhibition of hepatic enzyme metabolism; this may result in toxicity, obscuring therapeutic effects and worsening depression; may be dose-related, with lower doses of estrogens having less effect on enzyme inhibition than larger doses; dosage adjustments of the tricyclic may be necessary ^{06} ^{07} ^{08} ^{09})

Corticosteroids, glucocorticoid    (tricyclic antidepressants do not relieve, and may exacerbate, corticosteroid-induced mental depression ^{05})

Disulfiram^{125} or
Ethchlorvynol^{67}    (concurrent use with tricyclics, especially amitriptyline, may result in transient delirium)

    (also, CNS depressant effects may be increased when ethchlorvynol is used concurrently with tricyclic antidepressants)

Electroconvulsive therapy^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{123}^{124}    (although electroconvulsive therapy may be used in conjunction with tricyclic antidepressants, caution should be used as hazards may be increased)

» Extrapyramidal reaction–causing medications, other (See Appendix II )    (concurrent use with amoxapine and possibly other tricyclic antidepressants may increase the severity and frequency of extrapyramidal effects)

Fluoxetine    (concurrent use with tricyclic antidepressants has produced increased plasma concentrations of the tricyclic antidepressant ^{115} ^{126}, possibly due to inhibition of tricyclic antidepressant metabolism ^{126}; some clinicians recommend dosage reductions for tricyclic antidepressants of about 50% if used concurrently with fluoxetine ^{136} ^{137} ^{138} ^{189})

Methylphenidate^{39}^{112}^{123}^{125}    (serum concentrations of tricyclic antidepressants, especially desipramine and imipramine, may be increased due to inhibition of metabolism when methylphenidate is used concurrently; also, concurrent use may antagonize the effects of methylphenidate)

» Metrizamide    (administration of intrathecal metrizamide may lower the seizure threshold and increase the risk of seizures in patients taking tricyclic antidepressants; it is recommended that tricyclic antidepressants be discontinued for at least 48 hours before and at least 24 hours after myelography)

» Monoamine oxidase (MAO) inhibitors^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{121}^{122}^{123}^{124}^{125} , including furazolidone, procarbazine, and selegiline    (concurrent use with tricyclic antidepressants has resulted in an increased incidence of hyperpyretic episodes, severe convulsions, hypertensive crises, and death; however, recent studies have shown that concurrent use of some tricyclic antidepressants with MAO inhibitors can be used for refractory depression with no adverse effects if both medications are initiated simultaneously at lower than usual doses, with doses being raised gradually thereafter, or if the MAO inhibitor is gradually added to the tricyclic, also at low doses; a tricyclic should not be added to an existing MAO inhibitor regimen; the tricyclic antidepressants most commonly used in this combined therapy are amitriptyline, doxepin, and trimipramine ^{94}; imipramine, desipramine, nortriptyline, protriptyline, and clomipramine are not recommended for use in such a regimen because of potential excessive stimulation ^{95})

Naphazoline, ophthalmic or
Oxymetazoline, nasal or ophthalmic or
Phenylephrine, nasal or ophthalmic or
Xylometazoline, nasal    (if significant systemic absorption occurs, concurrent use with tricyclic antidepressants may potentiate pressor effects of these medications ^{116})

Pimozide    (concurrent use with tricyclic antidepressants may potentiate cardiac arrhythmias, which are seen on ECG as prolongation of the QT interval)

Probucol^{132}    (additive QT interval prolongation may increase risk of ventricular tachycardia)

» Sympathomimetics^{02}^{19}^{20}^{39}^{69}^{112}^{113}^{116}^{117}^{118}^{120}^{123}^{124}^{125}    (concurrent use with tricyclic antidepressants may potentiate cardiovascular effects possibly resulting in arrhythmias, tachycardia, or severe hypertension or hyperpyrexia; phentolamine can control the adverse reaction)

    (significant systemic absorption of ophthalmic epinephrine may also potentiate cardiovascular effects; also, local anesthetics with vasoconstrictors should be avoided or a minimal amount of the vasoconstrictor should be used with the local anesthetic)

    (concurrent use with tricyclic antidepressants may decrease the pressor effect of ephedrine and mephentermine)

Thyroid hormones^{112}^{113}^{115}^{116}^{117}^{118}    (concurrent use with tricyclic antidepressants may increase the therapeutic and toxic effects of both medications, possibly due to increased receptor sensitivity to catecholamines; toxic effects include cardiac arrhythmias and CNS stimulation ^{45})

Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
ECG    (changes include prolonged PR intervals, widened QRS complexes, and inverted or flattened T-waves ^{39} ^{69} ^{113} ^{114} ^{123} ^{124} ^{167} ^{168})

Metyrapone test    (amitriptyline may decrease the response to metyrapone ^{129})

With physiology/laboratory test values
Blood sugar concentrations    (may be increased or decreased ^{39} ^{69} ^{113} ^{115} ^{116} ^{117} ^{118} ^{119} ^{120} ^{123} ^{124})

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Note: This medication should not be used during the acute recovery period following a myocardial infarction.

Risk-benefit should be considered when the following medical problems exist
» Alcoholism, active^{112}^{116}^{117}^{119}    (CNS depression may be potentiated)

» Asthma    (may be aggravated)

» Bipolar disorder    (swing to hypomanic or manic phase may be accelerated ^{39} ^{69} ^{113} ^{115} ^{116} ^{117} ^{118} ^{119} ^{120} ^{121} ^{123} ^{124} and reversible rapid cycling between mania and depression may be induced by antidepressants in some patients; tricyclic antidepressant may have to be discontinued and lithium considered for a sustained remission ^{49} ^{77})

» Blood disorders^{69}^{113}    (may be potentiated)

» Cardiovascular disorders^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{123}^{124} , especially in children and the elderly    (increased risk of arrhythmias, heart block, congestive heart failure, myocardial infarction, or stroke)

» Gastrointestinal disorders    (risk of paralytic ileus ^{69} ^{113})

Genitourinary disease    (may be masked by the use of imipramine for enuresis in children ^{14})

» Glaucoma, narrow-angle^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{121}^{122}^{123} , predisposition to or
» Increased intraocular pressure^{69}^{112}^{113}^{116}^{118}^{119}^{123}^{124}    (may be aggravated)

» Hepatic function impairment^{39}^{69}^{112}^{113}^{116}^{123}    (metabolism of tricyclic may be altered)

» Hyperthyroidism^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{118}^{120}^{121}^{123}^{124}    (risk of cardiovascular toxicity)

» Prostatic hypertrophy    (risk of urinary retention)

» Renal function impairment^{39}^{69}^{112}^{123}    (excretion of tricyclic may be altered)

» Schizophrenia^{30}^{69}^{112}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{121}^{123}^{124}    (psychosis may be activated)

» Seizure disorders^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{121}^{123}^{124}    (seizure threshold may be lowered)

» Sensitivity to tricyclic antidepressants, carbamazepine, maprotiline, or trazodone^{39}^{69}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{121}^{122}^{123}^{161}
» Urinary retention^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{121}^{122}^{123}^{124}    (may be aggravated)

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood cell counts (usually during extended therapy and in patients with sore throat or fever)^{39}^{69}^{112}^{113}^{116}^{120}^{121}^{123} and
Blood pressure^{69} and pulse measurements and
Glaucoma tests and
Hepatic function determinations^{69}^{113}^{121} and
Renal function determinations    (may be required at periodic intervals during therapy to detect development of adverse effects that may not be evident to the patient ^{80})

Cardiac function monitoring^{69}^{116}    (ECG may be required in the elderly, in children, and in patients with existing cardiac disease, or in patients receiving antiarrhythmics such as quinidine, procainamide, or disopyramide, before initiation of therapy as a baseline and at periodic intervals thereafter)

    (for children taking imipramine for enuresis who are not responding to standard doses, ECG may be required before dosage is increased)

Careful supervision of depressed patients with suicidal tendencies^{112}^{116}    (recommended especially during early weeks of treatment; hospitalization may be required as a protective measure)

Dental examination    (recommended at least twice yearly ^{04})

Plasma tricyclic determinations    (recommended for patients who fail to respond to treatment, when there are increased side effects, when patient is at high risk, when there is doubt about patient compliance, or as a means of maximizing the response; optimum sampling time is immediately before the first morning dose or a minimum of 8 hours after a dose ^{76}; See Table 1 for therapeutic plasma concentration ranges ^{45})

For amoxapine (in addition to the above)
Careful observation for early signs of tardive dyskinesia^{119}    (recommended at periodic intervals, especially in the elderly; if early symptoms of tardive dyskinesia appear, amoxapine should be discontinued)

Side/Adverse Effects

Note: Although not all of these side effects have been attributed specifically to each tricyclic antidepressant, a potential exists for their occurrence during the use of any tricyclic antidepressant.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
For all tricyclic antidepressants

Anticholinergic effects (blurred vision^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{122}^{123}^{124}; confusion^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{121}^{122}^{123}^{124}; delirium or hallucinations^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{121}^{122}^{123}^{124}; constipation^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{121}^{122}^{123} , especially in the elderly^{118} , possibly resulting in paralytic ileus^{39}^{69}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{123}^{124}; difficult urination^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{121}^{122}^{123}^{124}; eye pain due to aggravation of glaucoma^{113})

fast, slow, or irregular heartbeat^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{121}^{122}^{123}^{124}

fine-muscle tremors, especially in arms, hands, head, and tongue^{69}^{78}^{112}^{116}^{117}^{118}^{119}^{120}^{121}^{123}^{124} (shakiness)

hypotension^{39}^{69}^{112}^{113}^{115}^{116}^{118}^{119}^{120}^{122}^{123}^{124} (fainting)

nervousness or restlessness^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{123}^{124}

Parkinsonian syndrome^{69}^{115}^{119}^{121}^{122}^{162} (difficulty in speaking or swallowing; loss of balance control; mask-like face; shuffling walk; slowed movements; stiffness of arms and legs; trembling and shaking of fingers and hands)

sexual function impairment^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{121}^{122}^{123}^{124} —more common with amoxapine and clomipramine^{150}^{176}

For amoxapine only (in addition to the above)

Tardive dyskinesia^{119} (lip smacking or puckering; puffing of cheeks; rapid or worm-like movements of tongue; uncontrolled chewing movements; uncontrolled movements of the arms or legs)

Incidence rare
For all tricyclic antidepressants

Agranulocytosis or other blood dyscrasias^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{121}^{122}^{123}^{124} (red or brownish spots on skin; sore throat and fever; unusual bleeding or bruising)

allergic reaction (increased sensitivity to sunlight; skin rash and itching; swelling of face and tongue)^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{121}^{122}^{123}^{124}

alopecia^{39}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{122}^{123}^{124} (hair loss)

anxiety^{69}^{112}^{115}^{116}^{118}^{119}^{120}^{124}

breast enlargement in both males and females^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{121}^{122}^{123}^{124} —more common with amoxapine

cholestatic jaundice^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{119}^{120}^{121}^{122}^{123}^{124} (yellow eyes or skin)

galactorrhea (inappropriate secretion of milk)—in females^{39}^{69}^{81}^{112}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{121}^{122}^{123}^{124}

seizures^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{118}^{119}^{122}^{123}^{124} —more common with clomipramine^{150}^{176}^{177}

syndrome of inappropriate secretion of antidiuretic hormone [SIADH]^{113}^{115}^{116}^{117}^{119}^{120}^{121}^{123}^{124} (irritability; muscle twitching; weakness)

testicular swelling^{39}^{69}^{115}^{116}^{117}^{118}^{119}^{120}^{122}^{123}^{124} —more common with amoxapine

tinnitus^{39}^{112}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{121}^{122}^{123}^{124} (ringing, buzzing, or other unexplained noises in the ears)

trouble with teeth or gums^{112} —more common with clomipramine

For amoxapine only (in addition to the above)

Neuroleptic malignant syndrome (NMS)^{119} (convulsions; difficult or fast breathing; fast heartbeat or irregular pulse; fever; high or low [irregular] blood pressure; increased sweating; loss of bladder control; severe muscle stiffness; unusually pale skin; unusual tiredness or weakness)
Note: May occur after prolonged treatment or after combined treatment with tricyclic antidepressants and neuroleptics ^{02}.

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent

Drowsiness^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{121}^{122}^{123}^{124}

dryness of mouth^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{121}^{122}^{123}^{124}

headache^{69}^{112}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{121}^{122}^{123}^{124}

increased appetite^{112}^{118}^{119} —may include craving for sweets^{140}^{141}

nausea^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{121}^{122}^{123}^{124}

orthostatic hypotension^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{121}^{122}^{123}^{124} (dizziness)

tiredness or weakness, mild^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{122}^{123}^{124}

unpleasant taste^{39}^{112}^{113}^{115}^{117}^{118}^{119}^{120}^{122}^{123}^{124}

weight gain^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{122}^{123}^{124}

Incidence less frequent

Diarrhea^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{120}^{121}^{122}^{123}^{124}

excessive sweating^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{121}^{122}^{124}

heartburn^{39}^{112}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{121}^{122}^{123}^{124}

trouble in sleeping^{112}^{113}^{115}^{116}^{118}^{119}^{121} —more common with protriptyline, especially when taken late in the day

vomiting^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{118}^{119}^{120}^{122}^{123}^{124}

Those indicating possible withdrawal and the need for medical attention if they occur after medication is discontinued
Occurring upon abrupt withdrawal, due to cholinergic rebound
For all tricyclic antidepressants

Headache^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{118}^{120}^{121}^{123}^{124}

nausea^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{118}^{120}^{121}^{123}^{124} , vomiting^{112} , or diarrhea

trouble in sleeping^{112} , with vivid dreams

unusual excitement

Occurring with gradual withdrawal after long-term treatment
For all tricyclic antidepressants

Irritability^{112}

restlessness

trouble in sleeping, with vivid dreams

For amoxapine only (in addition to the above)

Tardive dyskinesia^{119} , withdrawal-emergent (lip smacking or puckering; puffing of cheeks; rapid or worm-like movements of tongue; uncontrolled chewing movements; uncontrolled movements of the arms and legs)

Overdose
For specific information on the agents used in the management of tricyclic antidepressant overdose, see:
   • Anesthetics, Inhalation (Systemic) monograph;
   • Charcoal, Activated (Oral-Local) monograph;
   • Diazepam in Benzodiazepines (Systemic) monograph;
   • Digitalis Glycosides (Systemic) monograph;
   • Lidocaine (Systemic) monograph;
   • Paraldehyde (Systemic) monograph;
   • Phenytoin in Anticonvulsants, Hydantoin (Systemic) monograph;
   • Physostigmine (Systemic) monograph;
   • Propranolol in Beta-adrenergic Blocking Agents (Systemic) monograph; and/or
   • Sodium Bicarbonate (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute

Confusion^{112}^{115}^{116}^{117}^{124}

convulsions^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{120}^{121}^{122}^{123}^{124} —more severe and refractory with amoxapine

disturbed concentration^{96}^{119}^{124}

drowsiness, severe^{39}^{69}^{112}^{113}^{116}^{121}^{122}^{123}

enlarged pupils^{39}^{96}^{115}^{116}^{121}^{122}^{123}^{124}

fast, slow, or irregular heartbeat^{39}^{69}^{112}^{115}^{116}^{120}^{121}^{122}^{123}^{124}

fever^{69}^{115}^{117}^{120}^{123}

hallucinations^{124}

restlessness and agitation^{39}^{69}^{112}^{113}^{115}^{116}^{117}^{120}^{121}^{122}^{123}^{124}

shortness of breath or troubled breathing^{39}^{69}^{112}^{115}^{116}^{117}^{120}^{121}^{122}^{123}

unusual tiredness or weakness, severe^{39}^{69}^{116}^{117}^{123}

vomiting^{39}^{69}^{112}^{115}^{116}^{117}^{120}^{121}^{122}^{123}^{124}

Treatment of overdose
Treatment is essentially symptomatic and supportive ^{119} ^{122}, possibly including:

To decrease absorption:
Emptying stomach with ^{32} gastric lavage ^{39} ^{69} ^{112} ^{113} ^{116} ^{117} ^{119} ^{121} ^{122} ^{123} ^{124}.

To enhance elimination:
Administering activated charcoal slurry ^{39} ^{112} ^{113} ^{115} ^{116} ^{119} ^{121} ^{122} ^{123} ^{124} repeatedly ^{32}, followed by a stimulant cathartic.

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