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• Tricyclics and Other Norepinephrine-reuptake Inhibitors 28:16.04.28

Associated Monographs

• Amitriptyline

• Amoxapine

• Clomipramine

• Desipramine

• Doxepin

• Imipramine

• Nortriptyline

• Protriptyline

• Trimipramine

Tricyclic antidepressants contain a 3-ring structure and differ structurally and pharmacologically from other currently available antidepressants (e.g., selective serotonin-reuptake inhibitors, monoamine oxidase inhibitors).

Major Depressive Disorder

Tricyclic antidepressants are used in the treatment of major depressive disorder. A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks).408 According to DSM-IV criteria, a major depressive episode includes at least 5 of the following 9 symptoms (with at least one of the symptoms being depressed mood or loss of interest or pleasure): depressed mood most of the day as indicated by subjective report (e.g., feels sad or empty) or observation made by others; markedly diminished interest or pleasure in all, or almost all, activities most of the day; significant weight loss (when not dieting) or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite; insomnia or hypersomnia; psychomotor agitation or retardation (observable by others, not merely subjective feelings of restlessness or being slowed down); fatigue or loss of energy; feelings of worthlessness or excessive or inappropriate guilt (not merely self-reproach or guilt about being sick); diminished ability to think or concentrate or indecisiveness (either by subjective account or as observed by others); and recurrent thoughts of death or a suicide attempt or suicidal ideation.408

Treatment of major depressive disorder generally consists of an acute phase (to induce remission), a continuation phase (to preserve remission), and a maintenance phase (to prevent recurrence).356,393,407 Various interventions (e.g., psychotherapy, antidepressant drug therapy, electroconvulsive therapy [ECT]) are used alone or in combination to treat major depressive episodes. Treatment should be individualized and the most appropriate strategy for a particular patient is determined by clinical factors such as severity of depression (e.g., mild, moderate, severe), presence or absence of certain psychiatric features (e.g., suicide risk, catatonia, psychotic or atypical features, alcohol or substance abuse or dependence, panic or other anxiety disorder, cognitive dysfunction, dysthymia, personality disorder, seasonal affective disorder), and concurrent illness (e.g., asthma, cardiac disease, dementia, seizure disorder, glaucoma, hypertension).356 Demographic and psychosocial factors as well as patient preference also are used to determine the most effective treatment strategy.356

While use of psychotherapy alone may be considered as an initial treatment strategy for patients with mild to moderate major depressive disorder (based on patient preference and presence of clinical features such as psychosocial stressors), combined use of antidepressant drug therapy and psychotherapy may be useful for initial treatment of patients with moderate to severe major depressive disorder with psychosocial issues, interpersonal problems, or a comorbid axis II disorder.356 In addition, combined use of antidepressant drug therapy and psychotherapy may be beneficial in patients who have a history of poor compliance or only partial response to adequate trials of either antidepressant drug therapy or psychotherapy alone.356

Antidepressant drug therapy can be used alone for initial treatment of patients with mild major depressive disorder (if preferred by the patient) and usually is indicated alone or in combination with psychotherapy for initial treatment of patients with moderate to severe major depressive disorder (unless ECT is planned).356 ECT is not generally used for initial treatment of uncomplicated major depression, but is recommended as first-line treatment for severe major depressive disorder when it is coupled with psychotic features, catatonic stupor, severe suicidality, food refusal leading to nutritional compromise, or other situations when a rapid antidepressant response is required.356 ECT also is recommended for patients who have previously shown a positive response or a preference for this treatment modality and can be considered for patients with moderate or severe depression who have not responded to or cannot receive antidepressant drug therapy.356 In certain situations involving severely depressed patients unresponsive to adequate trials of several individual antidepressant agents, adjunctive therapy with another agent (e.g., buspirone, lithium) or concomitant use of a second antidepressant agent (e.g., bupropion) has been used; however, such combination therapy is associated with an increased risk of adverse reactions, may require dosage adjustments, and (if not contraindicated) should be undertaken only after careful consideration of the relative risks and benefits.356,420,421 (See Drug Interactions: Monoamine Oxidase Inhibitors and see Selective Serotonin-Reuptake Inhibitors under Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)

Considerations in Choosing Antidepressants

A variety of antidepressant drugs are available for the treatment of major depressive disorder, including tricyclic antidepressants, selective serotonin-reuptake inhibitors (SSRIs) (e.g., citalopram, escitalopram, fluoxetine, paroxetine, sertraline), monoamine oxidase (MAO) inhibitors (e.g., phenelzine, tranylcypromine), and other antidepressants (e.g., bupropion, desvenlafaxine, duloxetine, maprotiline, nefazodone, trazodone, venlafaxine).356,456,466 Most clinical studies have shown that the antidepressant effect of usual dosages of tricyclic antidepressants in patients with major depression is comparable to that of usual dosages of SSRIs (e.g., fluoxetine, paroxetine, sertraline) or other antidepressants (e.g., nefazodone, trazodone).340,341,342,343,344,345,346,347,348,349,350,356,360,361,362,363,364,365,366,367,368,369,370,371,372,373,374 Studies that have compared various tricyclic antidepressants have not conclusively demonstrated superiority of one agent over another. The onset of action of tricyclic antidepressants appears to be comparable to that of SSRIs,340,349,351,375,376 although the onset of action of these drugs has been variably reported to be somewhat faster338,375 or slower337,342,350 than that of tricyclic antidepressants in some studies.337,338,342,348,349,375

Because response rates in patients with major depression are similar for most currently available antidepressants, the choice of antidepressant agent for a given patient depends principally on other factors such as potential adverse effects, safety or tolerability of these adverse effects in the individual patient, psychiatric and medical history, patient or family history of response to specific therapies, patient preference, quantity and quality of available clinical data, cost, and relative acute overdose safety.356 No single antidepressant can be recommended as optimal for all patients because of substantial heterogeneity in individual responses and in the nature, likelihood, and severity of adverse effects.356 In addition, patients vary in the degree to which certain adverse effects and other inconveniences of drug therapy (e.g., cost, dietary restrictions) affect their preferences.356

Patient Tolerance Considerations

Because of differences in the adverse effect profile between tricyclic antidepressants and SSRIs, particularly more frequent anticholinergic effects, cardiovascular effects, and weight gain with tricyclic antidepressants, SSRIs such as citalopram, escitalopram, fluoxetine, paroxetine, or sertraline may be preferred in patients in whom such effects are not tolerated or are of potential concern.340,341,342,343,344,345,346,349,350,352,356,366,377,378,379,380,454,455 The decreased incidence of anticholinergic effects associated with SSRIs compared with tricyclic antidepressants is a potential advantage, since tricyclic antidepressants may be discontinued early in unusually sensitive patients.346,350,356 In addition, some anticholinergic effects may become troublesome during long-term tricyclic antidepressant therapy (e.g., persistent dry mouth may result in tooth decay).356,373 Although MAO inhibitors are not anticholinergic, many of their adverse effects resemble anticholinergic symptoms.356 Certain adverse GI effects (e.g., nausea, anorexia) or nervous system effects (e.g., anxiety, nervousness, insomnia, weight loss) appear to occur more frequently with SSRIs than with other antidepressant agents and alternatives may be preferred in patients who cannot tolerate these effects or when these effects are a concern.340,342,343,345,346,350,356,377,378

Pediatric Considerations

The clinical presentation of depression in children and adolescents can differ from that in adults and generally varies with the age and developmental stages of the child.356,427 Younger children may exhibit behavioral problems such as social withdrawal, aggressive behavior, apathy, sleep disruption, and weight loss; adolescents may present with somatic complaints, self esteem problems, rebelliousness, poor performance in school, or a pattern of engaging in risky or aggressive behavior.356

Only limited data are available to date from controlled clinical studies evaluating various antidepressant agents in children and adolescents, and many of these studies have methodologic limitations (e.g., nonrandomized or uncontrolled, small sample size, short duration, nonspecific inclusion criteria).427,428,429 However, there is some evidence that the response to antidepressants in pediatric patients may differ from that seen in adults, and caution should be used in extrapolating data from adult studies when making treatment decisions for pediatric patients.427,428,429 Results of several studies evaluating tricyclic antidepressants (e.g., amitriptyline, desipramine, imipramine, nortriptyline) in preadolescent and adolescent patients with major depression indicate a lack of overall efficacy in this age group.427,428 Based on the lack of efficacy data regarding use of tricyclic antidepressants and MAO inhibitors in pediatric patients and because of the potential for life-threatening adverse effects associated with the use of these drugs, many experts consider SSRIs the drugs of choice when antidepressant therapy is indicated for the treatment of major depressive disorder in children and adolescents.427,428,429 However, the US Food and Drug Administration (FDA) states that, while efficacy of fluoxetine in major depressive disorder has been established in pediatric patients, efficacy of other newer antidepressants (i.e., citalopram, duloxetine, escitalopram, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, venlafaxine) was not conclusively established in clinical trials in pediatric patients with major depressive disorder.437,438,439,440,444,454,455,456 In addition, FDA now warns that antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder and other psychiatric disorders.444,450,452 (See Cautions: Pediatric Precautions.) FDA currently states that anyone considering using an antidepressant in a child or adolescent for any clinical use must balance the potential risk of therapy with the clinical need.444,450 (See Cautions: Precautions and Contraindications.)

Geriatric Considerations

The response to antidepressants in geriatric patients is similar to that reported in younger adults, but depression in geriatric patients often is not recognized and is not treated.393,394,395,407 In geriatric patients with major depressive disorder, tricyclic antidepressants (e.g., amitriptyline) appear to be as effective as SSRIs (e.g., citalopram, escitalopram, fluoxetine, paroxetine, sertraline) but may cause more overall adverse effects than these other agents.350,387,388,407,454,455 Geriatric patients appear to be more susceptible to adverse effects of MAO inhibitors (e.g., episodes of hypertension, malignant hyperthermia) than younger patients, and these adverse effects are associated with increased morbidity in geriatric patients since they have less compensatory reserve to cope with any serious adverse reactions.419 Geriatric patients appear to be especially sensitive to anticholinergic (e.g., dry mouth, constipation, vision disturbance), cardiovascular, orthostatic hypotension, and sedative effects of tricyclic antidepressants.239,356,393,394,395 The low incidence of anticholinergic effects associated with SSRIs compared with tricyclic antidepressants is a potential advantage in geriatric patients, since some of these effects (e.g., constipation, dry mouth, confusion, memory impairment) may be particularly troublesome in these patients.346,350,352,356,367,380,381,394,395,407 Some clinicians state that SSRIs may be preferred for treating depression in geriatric patients in whom the orthostatic hypotension associated with tricyclic antidepressants potentially may result in injuries (such as severe falls).352 However, despite the fewer cardiovascular and anticholinergic effects associated with SSRIs, these drugs did not show any advantage over tricyclic antidepressants with regard to hip fracture in a case-control study.382 In addition, there was little difference in the rates of falls between nursing home residents receiving tricyclic antidepressants and SSRIs in a retrospective study.383 Therefore, all geriatric individuals receiving either type of antidepressant should be considered at increased risk of falls and appropriate measures should be taken.382,383

Patients with dementia of the Alzheimer's type (Alzheimer's disease, presenile or senile dementia) often present with depressive symptoms, such as depressed mood, appetite loss, insomnia, fatigue, irritability, and agitation.357,358 Most experts recommend that patients with dementia of the Alzheimer's type and depressive symptoms be considered as candidates for pharmacotherapy even if they fail to meet the criteria for a major depressive syndrome.357,358 The goals of such therapy are to improve mood, functional status (e.g., cognition), and quality of life.357,358 Although patients may present with depressed mood alone, the possibility of more extensive depressive symptomatology should be considered.357,358 Therefore, patients should be monitored carefully for indices of major depression, suicidal ideation, and neurovegetative signs since safety measures (e.g., hospitalization for suicidal ideation) and more vigorous and aggressive therapy (e.g., relatively high dosages, multiple drug trials) may be needed in some patients.357,358

If pharmacotherapy is initiated for depressive symptoms in Alzheimer's patients, most experts recommend SSRIs such as citalopram, escitalopram, fluoxetine, paroxetine, or sertraline as first-line therapy because of their favorable adverse effect profile in this population compared with other currently available antidepressants (e.g., tricyclic antidepressants, MAO inhibitors).357,358,430,454,455 Although evidence of efficacy from controlled studies currently is limited, the available evidence and experience with the use of antidepressants in patients with dementia of the Alzheimer's type and associated depressive manifestations indicate that depressive symptoms (including depressive mood alone and with neurovegetative changes) in such patients are responsive to antidepressant therapy.358,430 In some patients, cognitive deficits may partially or fully resolve during antidepressant therapy, but the extent of response will be limited to the degree of cognitive impairment that is directly related to depression.358 In a controlled study comparing paroxetine and imipramine in patients with coexisting depression and dementia, both drugs were found to be effective; however, paroxetine was better tolerated (fewer anticholinergic and serious adverse effects).359

Cardiovascular Considerations

Tricyclic antidepressants, MAO inhibitors, duloxetine, and trazodone are associated with orthostatic hypotension and tricyclic antidepressants also are associated with certain other cardiovascular effects (see Cautions: Cardiovascular Effects).456 The relatively low incidence of orthostatic hypotension and conduction disturbances reported to date with SSRIs may be advantageous in patients in whom cardiovascular effects may be hazardous.349,356,390,391 However, most clinical studies evaluating citalopram, escitalopram, fluoxetine, paroxetine, or sertraline for the management of depression did not include individuals with cardiovascular disease (e.g., those with a recent history of myocardial infarction or unstable heart disease) and further experience in such patients is necessary to confirm the reported relative lack of cardiotoxicity with SSRIs.340,348,390,391,454,455

Sedative Considerations

Because most tricyclic antidepressants frequently cause drowsiness and SSRIs are less sedating,340,342,348,349 some clinicians state that SSRIs may be preferable in patients who do not require sedative effects;349,356 however, a tricyclic antidepressant or some other agent with more prominent sedative effects may be preferable in some patients (e.g., those with insomnia).352,356

Suicidal Risk Considerations

Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.444,450,452 However, there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidal thinking and behavior (suicidality) in certain patients during the early phases of treatment.444 FDA states that antidepressants increased the risk of suicidality in short-term studies in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders.444,452 (See Cautions: Pediatric Precautions.) An increased suicidality risk was not demonstrated with antidepressants compared with placebo in adults older than 24 years of age, and a reduced risk was observed in adults 65 years of age or older.444,452 It is currently unknown whether the suicidality risk extends to longer-term antidepressant use (i.e., beyond several months); however, there is substantial evidence from placebo-controlled maintenance trials in adults with major depressive disorder that antidepressants can delay the recurrence of depression.444,452 Because the risk of suicidality in depressed patients may persist until substantial remission of depression occurs, appropriate monitoring and close observation of patients of all ages who are receiving antidepressant therapy are recommended.444 (See Cautions: Precautions and Contraindications.) Tricyclic antidepressants may produce potentially life-threatening cardiotoxicity following overdosage. Desipramine overdosage, in particular, has resulted in a higher death rate compared with overdosages of other tricyclic antidepressants.311,465,468 (See Acute Toxicity.)

Other Considerations

Tricyclic antidepressants and MAO inhibitors have the capacity to induce weight gain. In obese patients and/or patients in whom the increase in appetite, carbohydrate craving, and weight gain associated with tricyclic antidepressant therapy353,354 may be undesirable (e.g., potentially hazardous to the patient's health, result in possible discontinuance of or noncompliance with therapy), some clinicians state that other drugs (e.g., SSRIs) may be preferred since they possess anorectic and weight-reducing properties.340,341,342,343,344,345,346,349,350,352,353 However, the possibility that some patients with concurrent eating disorders or those who may desire to lose weight may misuse such drugs for their anorectic and weight-reducing effects should be considered.355

Panic Disorder

Tricyclic antidepressants (e.g., clomipramine, desipramine, imipramine) have been used effectively for the treatment of panic disorder with or without agoraphobia†.396,397,399,400,401,402,403,404,405,406,409 Although not clearly established, the antiphobic and antipanic effects of the drugs appear to be independent of their antidepressive action.

Panic disorder can be treated with cognitive and behavioral psychotherapy and/or pharmacologic therapy.409,412,414,416,417 There are several classes of drugs that appear to be effective in the pharmacologic management of panic disorder, including tricyclic antidepressants, MAO inhibitors (e.g., phenelzine), SSRIs (e.g., citalopram, fluoxetine, paroxetine, sertraline), and benzodiazepines (e.g., alprazolam, clonazepam).409,410,411,412,413,414,415,416,417 When choosing among the available drugs, clinicians should consider their acceptance and tolerability by patients; their ability to reduce or eliminate panic attacks, reduce clinically important anxiety and disability secondary to phobic avoidance, and ameliorate other common comorbid conditions (such as depression); and their ability to prevent relapse during long-term therapy.409,410,412,413,414,416,417 Because of their better tolerability when compared with other agents (such as the tricyclic antidepressants and benzodiazepines), the lack of physical dependence problems commonly associated with benzodiazepines, and efficacy in panic disorder with comorbid conditions (e.g., depression, other anxiety disorders such as obsessive-compulsive disorder, alcoholism), many clinicians prefer SSRIs as first-line therapy in the management of panic disorder.409,410,411,412,413,414,415,416,417 If SSRI therapy is ineffective or not tolerated, use of a tricyclic antidepressant or a benzodiazepine is recommended.409

In many patients receiving clomipramine, complete or nearly complete relief from panic attacks has been reported during therapy.399,400,402,403 For further information on use of clomipramine for the treatment of panic disorder, see Uses: Panic Disorder, in Clomipramine Hydrochloride 28:16.04.24.

Obsessive-Compulsive Disorder

Clomipramine is used in the treatment of obsessive-compulsive disorder.296 For information on use of clomipramine for the treatment of obsessive-compulsive disorder, see Uses: Obsessive-compulsive Disorder, in Clomipramine Hydrochloride 28:16.04.24.

Attention Deficit Hyperactivity Disorder

Tricyclic antidepressants have been used for the treatment of attention deficit hyperactivity disorder† (ADHD).315,316,317,318,321,431 Several studies that carefully evaluated the effect of tricyclic antidepressants (desipramine, imipramine) demonstrated positive effects on ADHD manifestations.431 Although tricyclic antidepressants generally have been shown to be effective in the management of ADHD, further evaluation of their safety and efficacy is needed and the drugs should be used cautiously in appropriately selected patients.315,316,317,321

Stimulants (e.g., methylphenidate, amphetamines) remain the drugs of choice for the management of ADHD.315,316,318,319,320,321,322,323,324,431 For patients who are intolerant of or unresponsive to stimulants, various other drugs (e.g., tricyclic antidepressants, bupropion, clonidine, guanfacine) have proven useful in clinical practice.315,316,318,320,321,431 These alternatives also may be useful in patients with comorbid conditions.316,321 However, experience with such alternative drug therapy is far less extensive than with stimulants, and conclusions regarding relative efficacy currently cannot be made.315,318,431

Tricyclic antidepressants generally have been shown to be effective in the management of ADHD in children and adolescents, but are associated with a narrower margin of safety than some other drugs.316,321 In addition, although a causal relationship has not been established, several cases of sudden death have been reported in children who received desipramine for ADHD† and have raised concerns about the use of this tricyclic in pediatric patients.311,315,316,317,321,431 (See Cautions: Pediatric Precautions.) Several clinical studies comparing tricyclic antidepressants with methylphenidate indicated either no difference in response or slightly better results with stimulants.431 Tricyclic antidepressants appear to be less effective than stimulants in improving attentional and cognitive symptoms, but may be useful for impulsive or hyperactive behavior.315 Tricyclic antidepressant therapy may be indicated as second-line therapy in patients who do not respond to stimulants or who develop clinically important depression or otherwise do not tolerate stimulants, but antidepressant therapy should be under the direction of a clinician familiar with use of the drugs.431 These antidepressants also may be useful for patients with tics or Tourette's disorder or in whom these conditions are exacerbated or not adequately controlled during stimulant therapy.315,316,321 Regardless of which tricyclic antidepressant is considered for use in the management of ADHD, the drugs should be used only if clearly indicated and with careful monitoring, including baseline and subsequent determinations of ECG and other parameters.316,321 For a more detailed discussion on the management of ADHD, see Uses: Attention Deficit Hyperactivity Disorder, in Methylphenidate 28:20.92.

Migraine

Tricyclic antidepressants also have been used for the prophylaxis of migraine headache†. The US Headache Consortium states that there is good evidence from multiple well-designed clinical trials that amitriptyline has medium to high efficacy for the prophylaxis of migraine headache and considers the drug to have mild to moderate adverse effects when used for this indication.432 Consistent evidence of efficacy is lacking for other antidepressants.432 For further information on management and classification of migraine headache, see Vascular Headaches: General Principles in Migraine Therapy, under Uses in Sumatriptan 28:32.28.

Enuresis

Imipramine hydrochloride is used as temporary adjunctive therapy in the treatment of functional enuresis in children 6 years of age or older.205 Other tricyclic antidepressants also have been used effectively for the treatment of enuresis†. Organic causes of enuresis should be ruled out before treatment with tricyclic antidepressants is begun, as the effects of the drugs may mask underlying genitourinary disease. When patients exhibit symptoms such as daytime urgency and frequency, appropriate examinations such as voiding cystourethrography and cystoscopy should be conducted. Relapses may occur following discontinuance of tricyclic antidepressants or even during therapy. Safety of imipramine or other tricyclic antidepressants for long-term, chronic use as adjunctive therapy for nocturnal enuresis has not been established; therefore, after a satisfactory response has been maintained, the drugs should be withdrawn gradually.

Eating Disorders

Tricyclic antidepressants (e.g., amitriptyline, desipramine, imipramine) have been used effectively in the management of eating disorders†, principally bulimia nervosa†.252,253,254,255,256,257,258,259,260,261,262,263,264,265,266,267,268,269,270,271,272,273,274,275,422 In patients with bulimia nervosa, therapy with the drugs has reduced substantially the frequency of binge eating, vomiting, and purging (laxative abuse) and the preoccupation with food.252,253,254,255,256,257,258,259,260,261,262,263,264,265,266,267,268,269,270,271,272,273,274,275 Although tricyclic antidepressant therapy also has improved associated depressed mood in many patients with this condition, reduction of bulimic manifestations by the drugs does not appear to depend on improvement in mood or the presence of concomitant depression.252,253,254,255,256,257,258,259,260,261,262,263,264,265,266,267,268,269,270,271,272,273,274,275

Experience with tricyclic antidepressants in the management of anorexia nervosa† is limited, and the possible role of the drugs in the management of this condition remains to be more fully elucidated.252,261,262,276,277,278,279 However, some clinicians state that tricyclic antidepressants may be useful for associated depression.261,262,422

Because malnourished depressed patients may be particularly susceptible to the adverse cardiovascular effects or other severe toxicities (including death) of tricyclic antidepressants, the American Psychiatric Association (APA) states that these agents should be avoided in underweight individuals and in those exhibiting suicidal ideation.422 For further information on use of antidepressants in the treatment of eating disorders, see Uses: Eating Disorders, in Fluoxetine Hydrochloride 28:16.04.20.

Smoking Cessation

Tricyclic (e.g., nortriptyline) and other (e.g., extended-release bupropion) antidepressants have been used for the management of nicotine (tobacco) dependence†.423 Although bupropion currently is considered first-line therapy for the management of nicotine dependence, the US Public Health Service (USPHS) currently recommends tricyclic antidepressant therapy with nortriptyline as second-line therapy for use under the supervision of a clinician.423 This recommendation is based on evidence from pooled analysis of 2 clinical studies on smoking cessation showing that nortriptyline therapy increased abstinence rates relative to placebo.423 Second-line pharmacotherapy (e.g., clonidine, nortriptyline, combined therapy with 2 forms of nicotine replacement) is of a more limited role than first-line pharmacotherapy (i.e., bupropion [as extended-release tablets], nicotine polacrilex gum, transdermal nicotine, nicotine nasal spray, nicotine nasal inhaler) in part because of more concerns about potential adverse effects with second-line drugs than with first-line drugs.423 The use of second-line pharmacotherapy should be considered after first-line pharmacotherapy was attempted or considered and should be individualized based on patient considerations.423 Use of second-line pharmacotherapy for smoking cessation should be considered for patients who received first-line drugs but were not able to quit smoking or in whom these drugs are contraindicated.423 (See Guidelines under Uses: Smoking Cessation, in Nicotine 12:92.)

Nicotine dependence therapy with an antidepressant may be particularly useful when a depressive disorder is included in the current or past history of patients attempting to quit smoking.423

Although it is not necessary to assess for possible comorbid psychiatric disorders prior to initiating therapy for nicotine dependence, such comorbidity is important in the assessment and treatment of nicotine-dependent patients since psychiatric disorders are common in this population, smoking cessation or nicotine withdrawal may exacerbate the comorbid condition, and patients with psychiatric comorbidities have an increased risk for relapse to smoking after a cessation attempt.423 However, even though some smokers may experience exacerbation of a comorbid condition with smoking cessation, most evidence suggests that abstinence entails little adverse impact.423 In addition, while psychiatric comorbidity places smokers at increased relapse risk, smoking cessation therapy still can be beneficial.423 Treatment of nicotine dependence can be provided concurrently with treatment of other chemical dependencies (alcohol and other drugs), and there currently is little evidence that patients with such dependencies relapse to other drug use when they stop smoking.423

Bipolar Disorder

Tricyclic antidepressants have been used to treat the depressive phase of bipolar disorder†, but do not prevent and may precipitate hypomanic or manic attacks in patients with this disorder. Tricyclic antidepressants appear to be associated with response rates equivalent to or poorer than other antidepressants (e.g., selective serotonin-reuptake inhibitors [SSRIs], bupropion) (although superior to placebo) and also may carry a greater risk of precipitating hypomania or manic episodes in patients with bipolar disorder than other classes of antidepressants.434

Depression Associated with Schizophrenia

Tricyclic antidepressants may be beneficial in the treatment of depressive stages of schizophrenia† or in the treatment of depression with psychotic features, although when given alone, they may precipitate psychotic or hostile behavior in individuals with these disorders. If the drugs are used for these patients, they should be administered with antipsychotic drugs such as phenothiazines.

Anxiety Disorders

Tricyclic antidepressants have been used to alleviate anxiety† in patients with psychoneurotic anxiety, anxiety associated with organic disease or alcoholism, and mixed symptoms of anxiety and depression. Occasionally, concurrent administration of tricyclic antidepressants with anxiolytics, sedatives, or antipsychotic drugs may be used in the treatment of depression with symptoms of anxiety, but treatment with an anxiolytic alone may also be successful. Detoxified alcoholics with mixed anxiety and depression and anxious depressed patients with a history of alcohol abuse appear more closely analogous to endogenous depressives than to reactive depressives and may respond better to tricyclic antidepressants than to conventional anxiolytics.

Postherpetic Neuralgia

Tricyclic antidepressants are considered by some clinicians to be among the drugs of choice for the symptomatic treatment of postherpetic neuralgia†.433 The analgesic effects of these drugs appear to be independent of their antidepressant action.433 Although most studies of antidepressant use in the symptomatic treatment of postherpetic neuralgia have involved amitriptyline, nortriptyline has been shown to have equivalent analgesic effects and generally is better tolerated than amitriptyline.433 Alternatively, desipramine may be used in patients who experience unacceptable sedation while receiving nortriptyline. 433

Insomnia

Doxepin is used for the treatment of insomnia characterized by difficulties with sleep maintenance.467 Although other tricyclic antidepressants have occasionally been used as hypnotics in nondepressed patients†, conventional hypnotics generally are more effective and cause fewer serious adverse reactions.

Administration

Tricyclic antidepressants are administered orally. Amitriptyline hydrochloride and imipramine hydrochloride also have been given IM, but parenteral dosage forms of these drugs no longer are commercially available in the US. Clomipramine hydrochloride has been administered IM† or IV†, but a parenteral dosage form is not commercially available in the US.336

Although tricyclic antidepressants have been administered in up to 4 divided doses throughout the day, the drugs are long-acting and the entire oral daily dose may be administered at one time. Administration of single daily doses may improve patient compliance. Administration of the entire daily dose at bedtime may promote sleep, reduce daytime sedation, and possibly reduce the awareness of other adverse effects. Patients who experience insomnia and stimulation from the drugs may receive the entire daily dose in the morning.

Dosage

There is a wide range of tricyclic antidepressant dosage requirements among patients, and dosage must be carefully individualized. Monitoring of plasma drug concentrations may be useful depending on the specific drug administered and clinical situation.208 Initially, tricyclic antidepressants are usually given in small dosages which are gradually increased according to the response and tolerance of the patient. Hospitalized patients under close supervision may generally be given higher dosages than outpatients; geriatric and adolescent patients should usually be given lower than average dosages. Maximum antidepressant effects may not occur for 2 or more weeks after therapy is begun.

After symptoms are controlled, dosage should be gradually reduced to the lowest level which will maintain relief of symptoms. The duration of tricyclic antidepressant therapy depends on the condition being treated, but maintenance therapy is usually continued for several months after a remission is achieved. To avoid the possibility of precipitating withdrawal symptoms, tricyclic antidepressants should not be terminated abruptly in patients who have received a high dosage for a prolonged period.

Patients receiving tricyclic antidepressants should be monitored for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustment.444,450,452 (See Cautions: Precautions and Contraindications.)

Minor adverse effects associated with tricyclic antidepressants generally reflect the drugs' anticholinergic and CNS activities. Serious reactions requiring discontinuance of therapy are relatively rare. Tolerance usually develops to sedative and anticholinergic effects and to postural hypotension; therefore, these adverse effects can be minimized by starting therapy with a low dosage and gradually increasing the dosage. Although all of the following adverse effects have not been reported for each tricyclic antidepressant, the possibility that each reaction may occur with any of the drugs should be kept in mind.

Anticholinergic Effects

The most common adverse effects of tricyclic antidepressants are those which result from anticholinergic activity. These include dry mucous membranes (occasionally associated with sublingual adenitis), blurred vision resulting from mydriasis and cycloplegia, increased intraocular pressure, hyperthermia, constipation, adynamic ileus, urinary retention, delayed micturition, and dilation of the urinary tract. The drugs have been reported to reduce the tone of the esophagogastric sphincter and to induce hiatal hernia in susceptible individuals or to exacerbate the condition in patients with preexisting hiatal hernias. Tricyclic antidepressants should be withdrawn if symptoms of esophageal reflux develop; if antidepressant therapy is essential, a cautious trial of a cholinergic agent such as bethanechol used concomitantly with the antidepressant may be warranted. Anticholinergic effects appear to occur most frequently in geriatric patients, but constipation is frequent in children receiving tricyclic antidepressants for functional enuresis.

Nervous System Effects

Adverse CNS and neuromuscular effects occur frequently. Drowsiness is the most frequent adverse reaction to tricyclic antidepressants; weakness, lethargy, and fatigue are also common. Conversely, agitation, excitement, nightmares, restlessness, and insomnia have occurred. Headache also has been reported. Confusion, disturbed concentration, disorientation, delusions, and hallucinations may occur, most commonly in geriatric patients. Children receiving tricyclic antidepressants for functional enuresis may experience drowsiness, anxiety, emotional instability, nervousness, and sleep disorders. Although effects differ among individual patients, sedative effects are usually greatest with amitriptyline or doxepin and least with protriptyline.

Worsening of depression and/or emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior may occur with antidepressants.444,450,452,453 (See Cautions: Precautions and Contraindications.)

Exacerbation of hypomania, panic, troublesome hostility, anxiety, or euphoria may occur in patients receiving tricyclic antidepressants. Exacerbation of psychosis has occurred in patients with schizophrenia or paranoid symptoms treated with the drugs; patients with bipolar depression may shift to the manic phase. Such psychotic manifestations should be treated by decreasing the dosage of tricyclic antidepressant or by administering an antipsychotic agent with the antidepressant. Alteration in EEG patterns and occasionally seizures have occurred. Seizures are more common in children than in adults. Coma also has occurred.

Extrapyramidal symptoms, including abnormal involuntary movements and tardive dyskinesia, may occur in patients receiving tricyclic antidepressants. A persistent fine tremor may occur in young as well as older patients, while the parkinsonian syndrome, when it occurs, is most common in geriatric patients receiving high dosages. Other extrapyramidal effects include rigidity, akathisia, dystonia, oculogyric crisis, opisthotonos, dysarthria, and dysphagia. Like antipsychotic agents, amoxapine and amitriptyline (with or without concomitant drugs known to cause neuroleptic malignant syndrome [NMS]) have been associated with NMS, a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment. For additional information on NMS, see Extrapyramidal Reactions under Cautions: Nervous System Effects, in the Phenothiazines General Statement 28:16.08.24.

Peripheral neuropathy, dizziness, tinnitus, dysarthria, numbness, tingling and paresthesia, incoordination, ataxia or unsteadiness, and falling also have been reported in patients receiving tricyclic antidepressants.

Cardiovascular Effects

Postural hypotension may occur during tricyclic antidepressant therapy. Other cardiovascular effects of the drugs include T-wave abnormalities (primarily flattening of the T-wave) and other alterations in ECG patterns; conduction disturbances such as bundle branch blocks and atrioventricular blocks; various arrhythmias such as palpitation, tachycardia (including ventricular tachycardia and torsades de pointes), bradycardia, ventricular fibrillation, ventricular premature complexes, and ventricular extrasystoles; syncope; collapse; sudden death; hypotension; hypertension; thrombosis and thrombophlebitis; stroke; and congestive heart failure.311,451,468 In at least one patient (an 8-year-old boy) receiving desipramine for 2 years for hyperactivity†, collapse and sudden death occurred;311,468 sudden death also has been reported in other children receiving desipramine.311,315,316,317,468 (See Cautions: Precautions and Contraindications and see also Pediatric Precautions.)

Patients with preexisting cardiovascular disease may be especially sensitive to the cardiotoxicity of tricyclic antidepressants.311,465,468 In addition, those with disturbed eating behaviors (e.g., purging) that result in inadequate hydration and/or compromised cardiac status also may be at greater risk of severe adverse cardiovascular effects (e.g., hypotension, increased cardiac conduction time, arrhythmia).422

Hypertensive episodes have occurred during surgery in patients receiving tricyclic antidepressants, and the drugs should be discontinued several days prior to elective surgery. In patients with cardiovascular disease receiving therapeutic dosages of tricyclic antidepressants, the drugs have been reported to increase the incidence of sudden death.311,465,468 Although myocardial infarction has been attributed to therapy with tricyclic antidepressants, a causal relationship has not been established.

Hematologic Effects

Rarely, agranulocytosis, thrombocytopenia, eosinophilia, leukopenia, and purpura have been reported and may be hypersensitivity reactions. Death related to eosinophilia has been reported in at least one adolescent (14 years of age) receiving desipramine therapy.424 Leukocyte and differential counts should be performed in all patients who develop symptoms of blood dyscrasias, such as sore throat and fever, and tricyclic antidepressants should be discontinued if evidence of pathologic neutrophil depression is found.

Hepatic Effects

Asymptomatic increases in serum aminotransferase (transaminase) concentrations, changes in serum alkaline phosphatase concentrations, obstructive-type jaundice, and hepatitis which appear to be allergic in nature have also occurred during therapy with tricyclic antidepressants. Elevated values on liver function tests indicate the need for repeat tests; if progressive elevations occur, the drugs should be discontinued. Jaundice and hepatitis are reversible following discontinuance of the drugs; however, deaths resulting from hepatitis have occurred when tricyclic antidepressants were continued. Hepatic failure has been reported in patients receiving amitriptyline; however, a causal relationship to the drug could not be established.

Sensitivity Reactions

Allergic manifestations have included rash and erythema, petechiae, urticaria, pruritus, eosinophilia, edema (general or of face and tongue), drug fever, and photosensitivity. Patients who demonstrate photosensitivity should avoid exposure to sunlight. A lupus-like syndrome (migratory arthritis, positive ANA and rheumatoid factor) has been reported in patients receiving amitriptyline; however, a causal relationship to the drug could not be established.

GI Effects

Adverse GI effects such as anorexia, nausea and vomiting, diarrhea, abdominal cramps, increases in pancreatic enzymes, epigastric distress, stomatitis, peculiar taste, and black tongue have been reported in patients receiving tricyclic antidepressants. Ageusia has been reported in patients receiving amitriptyline; however, a causal relationship to the drug could not be established.

Endocrine and Genitourinary Effects

Endocrine and genitourinary effects that have occurred in patients receiving tricyclic antidepressants include increased or decreased libido, impotence, testicular swelling, painful ejaculation, anorgasmia, breast engorgement and galactorrhea in females, gynecomastia in males, and elevation or lowering of blood glucose concentrations. The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) also has been reported.

Paradoxically, urinary frequency and nocturia have been reported.

Other Adverse Effects

In addition, some patients have developed headache, alopecia, flushing, chills, diaphoresis, interstitial pneumonitis, parotid swelling, nasal congestion, increased appetite, and weight gain or loss.

Precautions and Contraindications

Worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior may occur in both adult and pediatric (see Cautions: Pediatric Precautions) patients with major depressive disorder or other psychiatric disorders, whether or not they are taking antidepressants.444,450,452,453 This risk may persist until clinically important remission occurs.444,452 Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.444,450,452 However, there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.444 Pooled analyses of short-term, placebo-controlled studies of antidepressants (i.e., selective serotonin-reuptake inhibitors and other antidepressants) have shown an increased risk of suicidality in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders.444,452 An increased suicidality risk was not demonstrated with antidepressants compared with placebo in adults older than 24 years of age, and a reduced risk was observed in adults 65 years of age or older.444,452 It currently is unknown whether the suicidality risk extends to longer-term use (i.e., beyond several months); however, there is substantial evidence from placebo-controlled maintenance trials in adults with major depressive disorder that antidepressants can delay the recurrence of depression.444,452

The US Food and Drug Administration (FDA) recommends that all patients being treated with antidepressants for any indication be appropriately monitored and closely observed for clinical worsening, suicidality, and unusual changes in behavior, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.444,450,452 Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, also should be advised to monitor patients on a daily basis for the emergence of agitation, irritability, or unusual changes in behavior as well as the emergence of suicidality, and to report such symptoms immediately to a health-care provider.444,450

Although a causal relationship between the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.444,450 Consequently, consideration should be given to changing the therapeutic regimen or discontinuing therapy in patients whose depression is persistently worse or in patients experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if such manifestations are severe, abrupt in onset, or were not part of the patient's presenting symptoms.444 If a decision is made to discontinue therapy, tricyclic antidepressant dosage should be tapered as rapidly as is feasible but with recognition of the risks of abrupt discontinuance.444 (See Dosage and Administration: Dosage.) FDA also recommends that the drugs be prescribed in the smallest quantity consistent with good patient management, in order to reduce the risk of overdosage.444

It is generally believed (though not established in controlled trials) that treating a major depressive episode with an antidepressant alone may increase the likelihood of precipitating a mixed or manic episode in patients at risk for bipolar disorder.444 Therefore, patients should be adequately screened for bipolar disorder prior to initiating treatment with an antidepressant; such screening should include a detailed psychiatric history (e.g., family history of suicide, bipolar disorder, and depression).444 Tricyclic antidepressants are not approved for use in treating bipolar depression.444 (See Uses: Bipolar Disorder.)

Tricyclic antidepressants should be used with caution in patients for whom excess anticholinergic activity could be harmful, such as those with benign prostatic hypertrophy, a history of urinary retention, increased intraocular pressure, or angle-closure glaucoma.311,468 Patients who exhibit symptoms of angle-closure glaucoma should not receive the drugs until the cause of the symptoms is determined, and glaucoma should be corrected before treatment with tricyclic antidepressants is initiated. Patients whose glaucoma is adequately controlled by drugs should be closely monitored during therapy with tricyclic antidepressants, because tricyclic antidepressants may precipitate an attack of angle-closure glaucoma. The risk of hyperthermia should be considered when tricyclic antidepressants are used concomitantly with other drugs possessing anticholinergic activity and/or that affect thermoregulation (e.g., antimuscarinics, phenothiazines), particularly during hot weather. The toxic potential of tricyclic antidepressants (e.g., cardiotoxic effects with overdosage) relative to available alternative therapies should be considered in clinical decisions.

Patients should be warned that tricyclic antidepressants may impair their ability to perform hazardous activities requiring mental alertness or physical coordination such as operating machinery or driving a motor vehicle.

Tricyclic antidepressants should be administered with caution to patients with thyroid disease or patients receiving thyroid agents.311,468 (See Drug Interactions: Thyroid Agents.)

Respiratory failure resulting from CNS depression has occurred in a patient with chronic bronchitis receiving a tricyclic antidepressant, and the drugs should be used cautiously in individuals with respiratory difficulties.

Tricyclic antidepressants may lower the seizure threshold and should be used with caution in patients with a history of seizure disorders, organic brain disease, or who may be predisposed to seizures (e.g., in the acute withdrawal phase of alcoholism). The manufacturers of desipramine state that seizures may precede cardiac arrhythmias and death in some patients.311,465,468

Tricyclic antidepressants are contraindicated in the acute recovery phase following myocardial infarction. The drugs should be used with extreme caution in patients with preexisting cardiovascular disease because tricyclic antidepressants may cause adverse cardiovascular effects.311,468 The manufacturers of desipramine also state that the drug should be used with extreme caution in patients who have a family history of sudden death, cardiac arrhythmias, or cardiac conduction disturbances.311,465,468 (See Cautions: Cardiovascular Effects.) If use of tricyclic antidepressants in patients with preexisting cardiovascular disease is deemed essential, patients should be closely monitored and ECG tracings performed periodically. In addition, all patients receiving higher than usual dosages should have periodic ECG tracings, regardless of the presence or absence of cardiac abnormalities prior to treatment.

Individual tricyclic antidepressants are contraindicated in patients who have demonstrated hypersensitivity to them. Cross-sensitivity among the drugs has been reported, and should be considered when switching patients from one tricyclic antidepressant to another because of a hypersensitivity reaction.

The manufacturers of amitriptyline hydrochloride and protriptyline hydrochloride state that these drugs are contraindicated in patients taking cisapride because of the possibility of adverse cardiac effects, including cardiac arrhythmias and conduction disturbances (e.g., prolongation of the QT interval).

Pediatric Precautions

Safety and efficacy of amitriptyline,239 amoxapine,236 clomipramine,328 desipramine,311,468 nortriptyline,392 protriptyline,200 or trimipramine240 in pediatric patients have not been established. The manufacturers state that amoxapine should not be used in children younger than 16 years of age,236 amitriptyline should not be used in children younger than 12 years of age,239,418 and clomipramine should not be used in children younger than 10 years of age.328 Use of doxepin in children younger than 12 years of age for depressive and/or anxiety disorders is not recommended because safety has not been established;469 safety and efficacy of doxepin for insomnia in pediatric patients have not been established.467

Imipramine is used for the treatment of enuresis in children 6 years of age or older, but safety and efficacy of the drug for the treatment of enuresis in younger children or for the treatment of any other condition in pediatric patients have not been established.205

Collapse and sudden death occurred in at least one child (an 8-year-old boy) receiving desipramine for 2 years for attention deficit hyperactivity disorder†311,468 and sudden death also has been reported in other children receiving the drug.311,315,316,317,431,468 Although a causal relationship between the use of desipramine and the risk of sudden death has not been established, many clinicians recommend that desipramine not be used for the treatment of attention deficit hyperactivity disorder in children when tricyclic antidepressant therapy is contemplated.315,316,317

In addition, FDA warns that antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder and other psychiatric disorders.444,450,452 The risk of suicidality for these drugs was identified in a pooled analysis of data from a total of 24 short-term (4-16 weeks), placebo-controlled studies of 9 antidepressants (i.e., bupropion, citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, venlafaxine)446 in over 4400 children and adolescents with major depressive disorder, obsessive-compulsive disorder (OCD), or other psychiatric disorders.444,452 The analysis revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in pediatric patients receiving antidepressants than in those receiving placebo.444,452 The average risk of such events was 4% among children and adolescents receiving these drugs, twice the risk (2%) that was observed among those receiving placebo.444,452 However, a more recent meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients younger than 19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or suicidal ideation.453 No suicides occurred in these pediatric trials.444,452,453

The risk of suicidality in the FDA's pooled analysis differed across the various psychiatric indications, with the highest incidence observed in the major depressive disorder studies.444,452 In addition, although there was considerable variation in risk among the antidepressants, a tendency toward an increase in suicidality risk in younger patients was found for almost all drugs studied.444,452 It is currently unknown whether the suicidality risk in pediatric patients extends to longer-term use (i.e., beyond several months).444,452

As a result of this analysis and public discussion of the issue, FDA has directed manufacturers of all antidepressants to add a boxed warning to the labeling of their products to alert clinicians of this suicidality risk in children and adolescents and to recommend appropriate monitoring and close observation of patients receiving these agents.444,452 (See Cautions: Precautions and Contraindications.) The drugs that are the focus of the revised labeling are all drugs included in the general class of antidepressants, including those that have not been studied in controlled clinical trials in pediatric patients, since the available data are not adequate to exclude any single antidepressant from an increased risk.444,448,452 In addition to the boxed warning and other information in professional labeling on antidepressants, FDA currently recommends that a patient medication guide explaining the risks associated with the drugs be provided to the patient each time the drugs are dispensed.444,445,450,452

Anyone considering the use of an antidepressant in a child or adolescent for any clinical use must balance the potential risk of therapy with the clinical need.444,450,453

Geriatric Precautions

Clinical experience to date with the various tricyclic antidepressants in geriatric patients has not identified any differences in responses between geriatric and younger adults.200,239,311,328 However, safety and efficacy of tricyclic antidepressants have not been systematically studied in geriatric patients.200,205,236,239,240,311,392,418

In pooled data analyses, a reduced risk of suicidality was observed in adults 65 years of age or older with antidepressant therapy compared with placebo.444,452 (See Cautions: Precautions and Contraindications.)

Most manufacturers recommend that therapy in geriatric patients be initiated cautiously using a low initial dosage200,205,236,239,240,311,392,418 and that patients be observed closely since renal, hepatic, and cardiovascular dysfunction and concomitant disease or other drug therapy are more common in this age group than in younger patients.200,239,311 Cardiovascular function, particularly arrhythmias and fluctuations in blood pressure, should be monitored.392 Geriatric patients appear to be especially sensitive to anticholinergic (e.g., dry mouth, constipation, vision disturbance), cardiovascular, orthostatic hypotension, and sedative effects of tricyclic antidepressants.239,393,394,395 Adverse hepatic events (principally characterized by jaundice and elevated liver enzymes) have been observed very rarely in geriatric patients and deaths associated with cholestatic liver damage have been reported in isolated instances.392

Renal damage manifested by confusion, disorientation, and increased BUN and serum creatinine concentration was reported in a geriatric patient receiving 300 mg of imipramine hydrochloride daily.

Plasma concentrations of the active nortriptyline metabolite, 10-hydroxynortriptyline, have been reported to be higher in geriatric patients than in younger patients.392

Geriatric patients may be at risk of drug-induced toxicity when treated with desipramine, a tricyclic antidepressant that is known to be eliminated mainly by the kidneys.311 In this patient population, the ratio of the principal metabolite, 2-hydroxydesipramine, to desipramine appears to be increased, most likely because of decreased renal elimination that occurs with aging.311 Therefore, particular attention should be paid to desipramine dosage and it may be useful to monitor renal function in these patients.311 Desipramine use in geriatric patients also has been associated with an increased risk of falling and mental confusion.311

Pregnancy and Lactation

Pregnancy

Safe use of tricyclic antidepressants in pregnancy has not been established.200,205,236,239,240,311,328,392,418 Teratogenic effects occurred in reproduction studies evaluating amitriptyline in mice, rats, and rabbits,239 and embryotoxicity, fetotoxic effects (intrauterine death, stillbirth, decreased birth weight), or decreased postnatal survival have been reported in reproduction studies in animals evaluating amoxapine,236 clomipramine,328 or trimipramine.240 Although a causal relationship was not established, fetal malformations (including limb deformities) and developmental delay have been reported in neonates whose mothers received a tricyclic antidepressant (e.g., amitriptyline, imipramine) during pregnancy.205,239 In addition, urinary retention, CNS effects (including lethargy), and withdrawal symptoms (including jitteriness, tremor, seizures) have occurred in neonates whose mothers received a tricyclic antidepressant during pregnancy.239,328 Tricyclic antidepressants should not be used in pregnant women or women who may become pregnant unless the possible benefits outweigh the potential risks to the fetus.

Smoking cessation programs consisting of behavioral and educational rather than pharmacologic interventions should be tried in pregnant women before drug therapy is considered.423 Smoking cessation† therapy with a tricyclic antidepressant (e.g., nortriptyline), which is a second-line agent, should be used during pregnancy only if the increased likelihood of smoking cessation, with its potential benefits, justifies the potential risk to the fetus and patient of tricyclic therapy and possible continued smoking, and first-line pharmacotherapy (e.g., bupropion, nicotine replacement) has failed.423 Although smoking cessation prior to conception or early in pregnancy is most beneficial, health benefits result from cessation at anytime; therefore, effective smoking cessation interventions should be offered at the first prenatal visit and persist throughout the course of pregnancy for women who continue smoking after conception.423

Lactation

Amitriptyline,201,202 amoxapine,203,236 clomipramine,328 desipramine,204 doxepin,206,235 imipramine,204 and nortriptyline201,202 are distributed into milk, and it is likely that other tricyclic antidepressants also are distributed into milk.204 There has been at least one report of apnea and drowsiness in a nursing infant whose mother was receiving doxepin.418,467,469 Because of the potential for serious adverse reactions to tricyclic antidepressants in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Monoamine Oxidase Inhibitors

Concomitant administration of tricyclic antidepressants and monoamine oxidase (MAO) inhibitors is contraindicated, and it generally is recommended that at least 2 weeks should elapse between discontinuance of tricyclic antidepressant therapy or MAO inhibitor therapy and initiation of therapy with the other class of drugs.200,205,236,239,240,311,328,392,418 Serious, sometimes fatal, reactions including hyperpyrexia, confusion, diaphoresis, myoclonus, rigidity, seizures, cardiovascular disturbances, and coma have occurred in patients who received a tricyclic antidepressant and an MAO inhibitor concomitantly.328,329,330,331,332,333,335 Patients receiving therapeutic dosages of an oral tricyclic antidepressant and an oral MAO inhibitor concomitantly generally have experienced nonfatal hyperpyrexia, hypertension, tachycardia, confusion, and seizures; most reported cases of hyperpyretic crises, severe seizures, or death occurred following overdosage or parenteral administration of 1 or both drugs. Although the mechanism has not been clearly established, these reactions resemble serotonin syndrome and may be caused by excessive serotonergic activity in the CNS. The possibility of these reactions should also be considered in patients receiving tricyclic antidepressants and other drugs with MAO inhibitor activity (e.g., procarbazine).

For further information on serotonin syndrome, including manifestations and treatment, see Serotonin Syndrome under Drug Interactions: Drugs Associated with Serotonin Syndrome, in Fluoxetine Hydrochloride 28:16.04.20.

Hypotensive Agents

With the exception of doxepin in dosages less than 150 mg daily, tricyclic antidepressants block the uptake of guanethidine and similarly acting compounds into adrenergic neurons, and thus prevent their hypotensive activity.

Tricyclic antidepressants (i.e., imipramine, desipramine) have reportedly inhibited the hypotensive effect of clonidine. The increase in blood pressure usually occurs during the second week of tricyclic antidepressant therapy, but occasionally may occur during the first several days of concomitant therapy. The possibility of this interaction should be considered in patients receiving tricyclic antidepressants and clonidine concomitantly; blood pressure should be closely monitored during the first several weeks of concurrent therapy, and dosage of clonidine should be increased to adequately control hypertension if necessary. Alternatively, other hypotensive agents that do not interact with tricyclic antidepressants may be substituted, but clonidine therapy should not be discontinued abruptly. If tricyclic antidepressant therapy is discontinued in patients receiving clonidine, the hypotensive effect of clonidine may increase; blood pressure should be monitored and dosage of clonidine reduced if necessary. The possibility that this interaction may also occur in patients receiving guanabenz and tricyclic antidepressants concomitantly should also be considered. In rats, concurrent administration of clonidine and amitriptyline has produced corneal lesions within 5 days.

Tricyclic antidepressants may decrease the antihypertensive effect of rauwolfia alkaloids (no longer commercially available in the US). A stimulating effect has been reported in some depressed patients receiving tricyclic therapy after administration of reserpine.

CNS Depressants

Tricyclic antidepressants may be additive with or may potentiate the action of CNS depressants such as alcohol, sedatives, or hypnotics. Barbiturates may potentiate the adverse effects, including respiratory depression, produced by toxic doses of tricyclic antidepressants. With therapeutic doses of tricyclic antidepressants, barbiturates appear to stimulate metabolism and decrease blood concentrations of tricyclic antidepressants. The clinical importance of this effect has not been established, but the possibility of reduced therapeutic efficacy must be considered.

Concomitant administration of ethchlorvynol and amitriptyline has been reported to produce transient delirium. Pending further documentation of this interaction, ethchlorvynol should be used with caution in patients receiving tricyclic antidepressants.

Although some studies showed no substantial alteration of plasma tricyclic antidepressant concentrations during simultaneous administration of benzodiazepines, one study indicated that the half-life and steady-state plasma concentrations of amitriptyline may be increased in patients receiving diazepam. The clinical importance of this possible interaction has not been determined. There have been reports of impaired motor function when tricyclic antidepressants were used with benzodiazepines, but these have not been confirmed and the drugs have often been administered concomitantly with no adverse effects.

The manufacturer of protriptyline states that tricyclic antidepressants may increase the seizure risk in patients taking tramadol hydrochloride.

Antipsychotic Agents

Various phenothiazines and haloperidol have been shown to inhibit metabolism and increase blood concentrations of tricyclic antidepressants. Although the clinical importance has not been established, dosages of both drugs should be carefully adjusted whenever antipsychotics are given with tricyclic antidepressants.

Sympathomimetic and Anticholinergic Agents

Concomitant administration of tricyclic antidepressants with sympathomimetic drugs such as isoproterenol, phenylephrine, norepinephrine, epinephrine, or amphetamines may increase sympathetic activity to the extent that pressor and cardiac effects of the sympathomimetics could be fatal. If tricyclic antidepressants are used with adrenergic agents, dosage must be monitored closely.

Additive anticholinergic effects of tricyclic antidepressants and other agents with parasympatholytic activity require careful dosage adjustment if the drugs are given concomitantly. Concomitant administration of tricyclic antidepressants and anticholinergic agents has been reported to produce hyperthermia, particularly during hot weather, and paralytic ileus.

Drugs Affecting Hepatic Microsomal Enzymes

Tricyclic antidepressants are metabolized by various isoenzymes of the cytochrome P-450 (CYP) microsomal enzyme system, including CYP1A2, CYP2D6, CYP3A4, and CYP2C isoenzymes.325 (See Pharmacokinetics: Elimination.) Drugs that inhibit the activity of the cytochrome P-450 2D6 (CYP2D6) isoenzyme may increase plasma concentrations of tricyclic antidepressants to such an extent that extensive metabolizers of tricyclics may resemble poor metabolizers of the drugs. Drugs that inhibit cytochrome CYP2D6 include some drugs that are not metabolized by the enzyme (e.g., quinidine, cimetidine) and many that are substrates for CYP2D6 (e.g., flecainide, phenothiazines, propafenone, selective serotonin-reuptake inhibitors [SSRIs], other antidepressants). A patient who is stable on a given dose of a tricyclic antidepressant may abruptly experience symptoms of toxicity when given concomitant therapy with a drug that inhibits CYP2D6. Concomitant use of tricyclic antidepressants with drugs that inhibit CYP2D6 may necessitate lower dosages than usually prescribed for either the tricyclic or the other drug. In addition, whenever such drugs are discontinued, an increased dosage of the tricyclic antidepressant may be necessary. The manufacturers recommend that plasma concentrations of tricyclics be monitored whenever a tricyclic is coadministered with another drug known to be an inhibitor of CYP2D6.

Quinidine

Concomitant administration of quinidine and nortriptyline may result in a substantially longer plasma half-life, increased area under the plasma concentration-time curve, and decreased clearance of nortriptyline. In addition, quinidine reportedly decreased the clearance of desipramine and imipramine.325

Selective Serotonin-Reuptake Inhibitors

While all the selective serotonin-reuptake inhibitors (SSRIs) (e.g., citalopram, fluoxetine, paroxetine, sertraline) inhibit CYP2D6, there appears to be considerable variability among the SSRIs in the extent to which they inhibit this isoenzyme. Paroxetine and fluoxetine appear to be more potent in this regard than sertraline, fluvoxamine, venlafaxine, or citalopram (only weakly inhibitory).326,327

Fluvoxamine is a potent inhibitor of CYP1A2, and increased plasma concentrations (increases ranging from 1- to 8-fold) and clinical signs of tricyclic toxicity have occurred when the drug was administered in patients receiving amitriptyline, clomipramine, desipramine, or imipramine.325

The extent to which the interaction between SSRIs and tricyclic antidepressants may become clinically important depends on the extent of inhibition of the cytochrome isoenzymes and the pharmacokinetics of the concomitantly administered SSRI. Nevertheless, tricyclics and SSRIs should be used concomitantly with caution, and the dosage of the tricyclic should be reduced. In addition, the manufacturers of several tricyclics recommend a drug-free interval when switching from therapy with an SSRI to a tricyclic antidepressant. In particular, at least 5 weeks should elapse before initiating tricyclic antidepressant therapy in a patient being withdrawn from fluoxetine, given the long half-life of fluoxetine and its active metabolite.

Concurrent use of a tricyclic antidepressant (e.g., nortriptyline, desipramine, imipramine) and fluoxetine reportedly has resulted in adverse effects associated with tricyclic toxicity (including sedation, decreased energy, lightheadedness, psychomotor retardation, dry mouth, constipation, memory impairment)306,307,308,309,310 and/or greater than twofold elevations in plasma tricyclic antidepressant concentrations.306,307,308,309,310,311,312 There have been very rare cases of serotonin syndrome reported in patients receiving amitriptyline in conjunction with other serotonergic drugs.239

Cimetidine

Cimetidine, apparently through inhibition of hepatic microsomal enzyme systems, reduces the hepatic metabolism of some tricyclic antidepressants (i.e., amitriptyline, desipramine, imipramine).238,239,240,244,245 Concomitant administration of cimetidine and these tricyclic antidepressants may result in decreased tricyclic antidepressant clearance244 and increased bioavailabilities,238,243,244,247 elimination half-lives,241,242 or peak plasma238,239,246 and/or steady-state239,241,245,246 concentrations. Frequency and severity of antidepressant-induced adverse effects, especially anticholinergic effects, have increased during concomitant administration of cimetidine and tricyclic antidepressants.238,239 A reduction in tricyclic antidepressant dosage may be necessary if cimetidine is initiated in a patient receiving one of these antidepressants; conversely, an increase in dosage of the antidepressant may be necessary if cimetidine is discontinued.240 Ranitidine appears to be less likely to interact with tricyclic antidepressants than cimetidine.238,241,242

Levodopa

Tricyclic antidepressants may delay gastric emptying as a result of their anticholinergic activity. Absorption of drugs such as levodopa, which is absorbed from the intestine, may be delayed sufficiently to permit inactivation in the stomach. Careful dosage monitoring is essential when such drugs are administered with tricyclic antidepressants.

Anticoagulants

Nortriptyline and amitriptyline have been reported to increase plasma concentrations of dicumarol, and amitriptyline has also increased the prothrombin time in patients stabilized on warfarin. The mechanism is as yet unknown but may involve inhibition of anticoagulant metabolism or decrease in intestinal motility, thereby increasing the time available for absorption of the anticoagulant.

Cisapride

The manufacturers of amitriptyline hydrochloride and protriptyline hydrochloride state that these drugs are contraindicated in patients taking cisapride because of the possibility of adverse cardiac effects, including cardiac arrhythmias and conduction disturbances (e.g., prolongation of the QT interval).

Thyroid Agents

Levothyroxine and liothyronine have been reported to accelerate the onset of therapeutic effects of tricyclic antidepressants; however, concomitant use may also produce cardiovascular toxicity, including arrhythmias.311,468 Tricyclic antidepressants should be administered with extreme caution to patients who have thyroid disease or who are receiving thyroid agents.311,468

Methylphenidate

Methylphenidate has been reported to inhibit the metabolism of tricyclic antidepressants and to increase their effectiveness; presumably, the toxicity of tricyclic antidepressants could also be increased.

Antidiabetic Agents

Substantial hypoglycemia occurred in one patient with type 2 diabetes mellitus receiving chlorpropamide 250 mg daily after nortriptyline 125 mg daily was initiated.

Acute Toxicity

Pathogenesis

The toxic dose of tricyclic antidepressants varies considerably. Generally, tricyclic antidepressant doses of approximately 10-20 mg/kg are associated with moderate to severe toxicity, and doses of 30-40 mg/kg are often fatal in adults.216,217,219,221,233 The lowest known fatal adult dose of amitriptyline is 500 mg, but 1 patient survived after ingesting 10 g of the drug. Although the average acute lethal dose of imipramine for adults has been estimated to be 30 mg/kg, fatalities have occurred in adults who received 500 mg of the drug. Some patients have survived reported nortriptyline ingestions of up to 525 mg. Severe symptoms or death occur in children who receive more than 20 mg/kg of imipramine. Death was reported in a 5-year-old child who inadvertently received a single 500-mg dose of imipramine for the treatment of enuresis.425,426 Desipramine overdosage has resulted in a higher death rate compared with overdosages of other tricyclic antidepressants.311,465,468 Patients with preexisting cardiac disease, patients with disturbed eating behaviors (e.g., purging) that result in inadequate hydration and/or compromised cardiac status, and children appear to be somewhat more susceptible to tricyclic antidepressant-induced cardiotoxicity than healthy adults.217,233,422

The manufacturers state that ingestion of multiple drugs, including alcohol, is common in patients who deliberately ingest overdoses of tricyclic antidepressants.311,469

Manifestations

Overdosage of tricyclic antidepressants produces symptoms that are primarily extensions of common adverse reactions.

Following a latent period that may last approximately 1-12 hours, CNS stimulation, which may result in part from excess anticholinergic activity, usually occurs initially.221 Peripheral anticholinergic symptoms which occur in overdose include urinary retention, dry mucous membranes, mydriasis, constipation, and occasionally adynamic ileus.

Severe CNS depression usually follows the initial stimulation. The patient may exhibit extreme drowsiness, areflexia, hypothermia, respiratory depression, cyanosis, severe hypotension, depressed level of consciousness,451 and coma.

The most important cardiovascular effects of tricyclic antidepressants in overdosage are their quinidine-like effects on cardiac conduction,211,212,216,221 particularly decreased intraventricular conduction as manifested by QRS interval prolongation.210,211,212,213,214,215,216,217,218,219,220,221,222,233,311,465,468 Data suggest that ECG changes, particularly in the QRS axis or width (i.e., prolongation of the QRS interval to 100 msec or greater), may be clinically important indicators of the severity of tricyclic antidepressant overdosage212,214,216,219,220,221,233,311,465,468 (although possibly not in the case of amoxapine).231,233 The manufacturers of desipramine state that early changes in the QRS complex include a widening of the terminal 40 msec with a rightward axis in the frontal plane, which is recognized by the presence of a terminal S wave in lead 1 and AVL and an R wave in AVR.311,465,468 The manufacturers of desipramine further state that prolongation of the maximal limb-lead QRS interval to greater than 100 msec is a clinically significant indicator of desipramine toxicity, particularly for the risk of seizures and, eventually, cardiac dysrhythmias.311,465,468 Although QRS prolongation usually is associated with total plasma tricyclic concentrations greater than 1000 ng/mL,211,214,217,219,220,221 it is possible to have high plasma tricyclic concentrations without evidence of substantial ECG abnormalities.211,214,219,220 A fatal arrhythmia, which occurred as late as 56 hours after an amitriptyline overdose, has been reported.

Acid-base disturbances may occur in acute tricyclic intoxication.210,211,213,215,217 Acidosis, which appears to be the most frequent acid-base disturbance, may be metabolic and/or respiratory in origin210,211,213,215,217 and usually results from hypotension, hypoventilation, and/or seizures.210,211,215,224,233 Occasional manifestations of tricyclic antidepressant overdosage have included ataxia, dysarthria, bullous cutaneous lesions, vermiculation, polyradiculoneuropathy, renal failure, vomiting, and pulmonary consolidation.

Treatment

Treatment of tricyclic overdosage generally involves aggressive symptomatic and supportive care and serum alkalinization.311,468 Because signs and symptoms of toxicity may develop rapidly following tricyclic overdosage, hospital monitoring usually is required as soon as possible after ingestion.469 An ECG should be obtained and cardiac monitoring initiated immediately.311,468 Patients should be closely observed for a minimum of 6 hours for signs of CNS or respiratory depression, hypotension, seizures, and cardiac dysthythmias and/or conduction block. If signs of toxicity develop at any time during this period, extended monitoring is necessary. Late-onset, fatal dysrhythmias have been reported after an overdose; these patients had clinical evidence of substantial poisoning prior to death and most had received inadequate GI decontamination. Plasma concentrations of tricyclic antidepressants should not guide management of the patient. Support of cardiovascular and respiratory functions is critical. An adequate airway should be maintained; respiratory assistance may be necessary. The patient's temperature should be maintained; initial hyperthermia may be treated with ice packs, while patients with hypothermia should be kept warm. Fluid, acid-base, and electrolyte balance should be monitored frequently and corrected if necessary.451,468 In addition, renal function and plasma creatinine phosphokinase (CPK) concentrations should be monitored if clinically needed.468 External stimulation should be minimized to reduce the tendency to seizures.

Physical removal of tricyclic antidepressants from the GI tract generally should be attempted and activated charcoal administered to decrease absorption even several hours after ingestion, because the anticholinergic effects of the tricyclic antidepressants may delay gastric emptying and the drugs also may be secreted into the stomach.311,465,467,468,469 Gastric lavage, preferably followed by the instillation of activated charcoal, is sometimes recommended (since CNS depression can develop rapidly) if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents.467,469 Emesis generally is contraindicated in tricyclic intoxication.311,467,468,469 Tricyclic antidepressants are highly protein bound, so peritoneal dialysis and hemodialysis are not effective in removing the drugs. Forced diuresis also eliminates very little drug and may be dangerous if cardiac function is impaired.

IV benzodiazepines (e.g., diazepam) generally are considered to be the drugs of choice for treatment of seizures;209,210,211,212,215,216,217,218,219,233,311,467,468 however, they should be used with caution since respiratory and CNS depression may result.211,216,219,221 If benzodiazepines are ineffective or if seizures recur, other drugs with anticonvulsant activity (e.g., phenobarbital, propofol) may be used.311,465,468 Barbiturates generally should not be used as they may enhance respiratory depression, but the drugs may be useful in seizures refractory to diazepam.

In patients with substantial cardiovascular toxicity (e.g., QRS widening greater than 100 msec on the ECG, cardiac conduction disturbances and arrhythmias, hypotension), serum alkalinization with IV sodium bicarbonate (i.e., to achieve a systemic pH of 7.4-7.55) is recommended.210,211,212,216,217,218,219,221,233,311,451,465,469 Hyperventilation may be used to increase the pH if the response to sodium bicarbonate alone is inadequate.311,451,465 Some experts and manufacturers state that class IA (e.g., disopyramide, procainamide, quinidine), IC (e.g., flecainide, propafenone), and III (e.g., amiodarone, sotalol) antiarrhythmics and other antiarrhythmic agents that block the fast sodium channel generally are contraindicated in cases of poisoning with tricyclic antidepressants or other fast sodium channel blockers and in the management of conduction abnormalities and cardiac arrhythmias, because of the risk of synergistic toxicity (e.g., further depressed myocardial conduction and contractility).209,210,211,212,216,218,221,311,451,468 Administration of more than one antiarrhythmic agent may be required. Insertion of a temporary transvenous cardiac pacemaker may be necessary in patients with advanced AV block, severe bradycardia, and/or life-threatening ventricular arrhythmias unresponsive to drug therapy.209,210,211,212,216,219,221,230

Tricyclic overdosage may result in central (e.g., delirium, agitation, myoclonus, coma) and peripheral (e.g., urinary retention, constipation) anticholinergic manifestations, but these signs and symptoms are generally not life-threatening.211,216,217,221,459,463 Although physostigmine has been used successfully in the treatment of tricyclic-induced anticholinergic toxicity,210,211,212,216,217,218,221,459,461,462,463 the drug currently is rarely used because of its potential to cause serious adverse effects, including seizures, bronchospasm, and bradyarrhythmias (including asystole).210,211,217,218,221,451,459,460,461,462 The precise role of physostigmine in the management of tricyclic overdosage remains controversial; most clinicians advise against the routine use of physostigmine in such cases,209,210,211,212,215,216,217,218,221,451,459,462 and some clinicians recommend that the drug be reserved only for treatment of life-threatening anticholinergic symptoms refractory to other forms of treatment.211,217,221

Because the management of tricyclic antidepressant overdosage is complex and changing, clinicians should consult a poison control center for the most current information on treatment.311,468

Patients whose overdosage was deliberate should be monitored especially carefully during recovery to prevent additional suicide attempts, and mental health counseling is usually necessary prior to and following medical discharge.211,216,219,221

Chronic Toxicity

Abrupt withdrawal of tricyclic antidepressants following prolonged therapy and/or treatment with high doses may precipitate a syndrome consisting of akathisia, anxiety, chills, coryza, malaise, myalgia, headache, dizziness, nausea, and/or vomiting. In addition, irritability, restlessness, and dream and sleep disturbances reportedly may occur within 2 weeks when tricyclic antidepressant dosage is gradually reduced. Mania and hypomania have occurred rarely within 2-7 days following discontinuance of chronic tricyclic antidepressant therapy. Whether or not these symptoms are indicative of physical dependence is unclear.

Pharmacology

Nervous System Effects

Antidepressant Effect

The precise mechanism of antidepressant action of the tricyclic antidepressants is unclear, but the drugs have been shown to block, in varying degrees, the reuptake of various neurotransmitters at the neuronal membrane. The effects of norepinephrine and serotonin may thus be potentiated. In addition, tricyclic antidepressants exhibit strong anticholinergic activity. The antidepressant activity of these drugs may be related to any or all of these effects, although effects on norepinephrine and serotonin are generally regarded as the most important.

Effects on Animal Behavior

In animals, tricyclic antidepressants are similar to phenothiazines in their effects on various avoidance behavior. Unlike the phenothiazines, however, tricyclic antidepressants potentiate the effects of norepinephrine, serotonin, amphetamines, and certain other CNS stimulants. Tricyclic antidepressants do not inhibit monoamine oxidase (MAO).

Effects on Sleep

Tricyclic antidepressants produce varying degrees of sedation in patients with or without a history of depression.435 Tricyclic antidepressants decrease the number of awakenings, increase stage-4 sleep, and substantially increase the latency and decrease the total time spent in rapid eye movement (REM) sleep, which is typically more prominent and occurs earlier in the sleep of patients with depression.435 Tricyclic antidepressants appear to have greater sedative effects than secondary-amine antidepressants (bupropion) or selective serotonin-reuptake inhibitors (e.g., fluoxetine).435

Effects on EEG

Tricyclic antidepressants may produce abnormal EEG patterns in which the alpha activity decreases while theta activity increases. Some increase in delta, beta , and burst activity also occurs. The drugs also may lower the seizure threshold.

Enuresis

The mechanism of action of the tricyclic antidepressants in the treatment of enuresis is not known but may involve inhibition of urination due to anticholinergic activity, CNS stimulant activity resulting in easier arousal by the stimulus of a full bladder, and/or other mechanisms which are presently unknown.

Cardiovascular Effects

Tricyclic antidepressants have direct quinidine-like cardiotoxic properties which, in conjunction with indirect cardiac effects resulting from anticholinergic activity and potentiation of norepinephrine, may produce a variety of cardiovascular disturbances, such as ECG changes, tachycardia, and postural hypotension. (See Cautions: Cardiovascular Effects and see also Acute Toxicity.)

Other Effects

Therapeutic doses of tricyclic antidepressants do not affect respiration, but respiratory depression may occur following toxic doses. Tricyclic antidepressants may also affect the endocrine system, producing changes in the concentrations of sex hormones and blood glucose. In toxic doses, the drugs may alter temperature regulation; hyperpyrexia or hypothermia may result.

Pharmacokinetics

Absorption

Tricyclic antidepressants are well absorbed from the GI tract. Plasma concentrations exhibit considerable interpatient variation apparently because of genetic differences in rate of metabolism and differences in the amount of drug bound to proteins. Plasma concentrations of tricyclics may be elevated in patients with the poor-metabolizer phenotype. (See Pharmacokinetics: Elimination.) Such elevations may be slight or quite large (e.g., an eightfold increase in area under the plasma concentration-time curve) depending on the fraction of the drug that is metabolized by the cytochrome P-450 (CYP) 2D6 (CPY2D6) isoenzyme. Poor metabolizers may have an increased risk of adverse effects (e.g., cardiac toxicity) when receiving tricyclics that are metabolized principally by CYP2D.325,326

The relationship of plasma concentrations to clinical response and acute toxicity has not been fully established. A Task Force of the American Psychiatric Association concluded on the basis of available evidence that monitoring plasma concentrations of imipramine and nortriptyline (and probably desipramine) is definitely useful in patients who do not respond to usual dosages, in those at particular risk of toxicity because of age or existing illness, and in those whose treatment is considered urgent (e.g., potentially suicidal patients or those whose illness may jeopardize their work or ability to care for their family) and may be helpful in other situations (e.g., assessing compliance).208 The Task Force also concluded that for other currently available tricyclic antidepressants there were generally insufficient data to date to assess the value of and/or formulate recommendations for monitoring plasma concentrations.208 Adverse effects appear within a few hours after administration of the drugs, but full antidepressant effects may not occur for several weeks.

Distribution

Tricyclic antidepressants are distributed to the lungs, heart, brain, and liver. Tricyclic antidepressants and their active metabolites are highly bound to plasma and tissue proteins. Clomipramine, nortriptyline, and probably other tricyclic antidepressants, readily cross the placenta. Amitriptyline,201,202 amoxapine,203,236 clomipramine,328 desipramine,204 doxepin,206,235,418,467,469 imipramine,204 and nortriptyline201,202 are distributed into milk. It is likely that other tricyclic antidepressants are also distributed into milk.204

Elimination

Steady-state half-lives of tricyclic antidepressants exhibit wide interpatient variation.

Clomipramine, imipramine, and nortriptyline undergo first-pass metabolism in the liver when administered orally. Metabolism of tricyclic antidepressants by N -demethylation, N -oxidation, aromatic and aliphatic hydroxylation, dealkylation, and conjugation occurs in the liver.

Tricyclic antidepressants are metabolized by various isoenzymes of the cytochrome P-450 (CYP) microsomal enzyme system, including CYP1A2, CYP2D6, CYP3A4, and CYP2C isoenzymes, which are under genetic control.325 Genetic absence or inhibition of one isoenzyme may lead to compensation through a secondary isoenzyme pathway.325,326 However, genetic absence or inhibition of an isoenzyme may lead to increased drug toxicity.325 The ability to metabolize tricyclics via CYP2D6 is associated with the ability to oxidatively metabolize debrisoquin or dextromethorphan. Approximately 90-93% of Caucasians exhibit the extensive-oxidizer phenotype and about 7-10% the poor-oxidizer phenotype. The percentage of extensive- and poor-metabolizer phenotypes among Asian, African, and other populations has not been precisely determined, although it has been estimated that 1-3% of Asians and African-Americans are poor metabolizers of dextromethorphan. Individuals who extensively metabolize tricyclics via the CYP2D6 pathway exhibit the extensive-metabolizer phenotype, while those who have an impaired ability to metabolize the drugs by this pathway exhibit the poor-metabolizer phenotype.

Metabolites which are lipophilic, such as N -monodemethylated derivatives, can cross the blood-brain barrier and are pharmacologically active; metabolites formed by oxidation or hydroxylation and their glucuronide conjugates, however, are more polar and are probably pharmacologically less active. Enterohepatic circulation and secretion of the drugs and their metabolites into gastric juice may occur. Only small amounts of unchanged drugs and active metabolites are excreted; lipophilic metabolites are largely reabsorbed and further metabolized, while more polar derivatives are excreted. The primary route of elimination of the tricyclic antidepressants and their metabolites is urinary excretion, but they may also be excreted in feces via the bile. The rate of elimination varies among the drugs.

Chemistry

Amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, and trimipramine are classified as tricyclic antidepressants since they contain a 3-ring structure and possess antidepressant action. Maprotiline is a tetracyclic antidepressant that shares many of the pharmacologic actions and toxic potentials of the tricyclic antidepressants. Tricyclic antidepressants differ structurally and pharmacologically from other currently available antidepressants (e.g., selective serotonin-reuptake inhibitors, monoamine oxidase inhibitors).

Amitriptyline, desipramine, doxepin, imipramine, nortriptyline, and protriptyline contain 2 aromatic rings connected by a 7-membered ring to which is joined a propylamino side chain. Amoxapine, clomipramine, and trimipramine also contain 2 aromatic rings connected by a 7-membered ring, but these drugs have other side groups joined to the 7-membered ring. Maprotiline differs structurally from tricyclic antidepressants by the presence of an ethylene bridge in its center ring, resulting in a rigid flexure of its molecular structure.

Based on structure, the tricyclic antidepressants can be subdivided into dibenzazepine (iminodibenzyl), dibenzocycloheptene, or dibenzoxepin derivatives.

Dibenzazepine Derivatives

Imipramine, desipramine, clomipramine, and trimipramine are dibenzazepine-derivative tricyclic antidepressants. Desipramine is the N -monodemethylated metabolite of imipramine; clomipramine is the 3-chloro analog of imipramine. The dibenzazepine-derivative tricyclic antidepressants differ structurally from the antipsychotic phenothiazines in that an ethylene bridge replaces the sulfur atom in the phenothiazine nucleus.

Dibenzocycloheptene Derivatives

Amitriptyline, nortriptyline, and protriptyline are dibenzocycloheptene-derivative tricyclic antidepressants. Nortriptyline is the N -monodemethylated metabolite of amitriptyline. The dibenzocycloheptene-derivative tricyclic antidepressants differ structurally from the antipsychotic thioxanthenes in that an ethylene bridge replaces the sulfur atom in the thioxanthene nucleus. In protriptyline, the ethylene bridge in the center ring is unsaturated while the carbon atoms joining the propylamino group to the ring nucleus are saturated.

Dibenzoxepin Derivatives

Amoxapine and doxepin are dibenzoxepin-derivative tricyclic antidepressants. Amoxapine differs structurally from other currently available tricyclic antidepressants in that it has both a nitrogen and an oxygen atom in its 7-membered ring and a piperazinyl ring attached to the center ring. Doxepin differs structurally from amitriptyline in that an oxygen atom is substituted for a carbon atom in the center ring.

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