Chapter 9 Tricyclic and Tetracyclic Drugs

CHAPTER 9 Tricyclic and Tetracyclic Drugs

J. Craig Nelson, M.D.

The tricyclic antidepressant agents hold an important place in the history of treatments for depression. They were the first class of antidepressant compounds to be widely used in depression and remained the first-line treatment for more than 30 years. The observation of their activity led to theories of drug action involving norepinphrine and serotonin. Indeed, this “psychopharmacological bridge” suggested that alterations of these neurotransmitters might cause depression (Bunney and Davis 1965; Prange 1964; Schildkraut 1965). The tricyclics were extensively studied, and through this study, the field developed several key principles to guide the management of depressive illness. For example, the importance not only of providing an adequate dosage and duration of medication during acute treatment but also of sustaining symptom improvements through the use of continuation treatment became recognized. The adverse events associated with the tricyclics required that psychiatrists become familiar with a variety of syndromes, such as anticholinergic delirium, delayed cardiac conduction, and orthostatic hypotension. The observation that tricyclic plasma concentrations varied widely stimulated interest in the relationship of these drug concentrations to hepatic metabolism and to clinical activity. The field was introduced to the concepts of genetic polymorphisms in the cytochrome P450 (CYP) enzyme system. Finally, our knowledge of how these drugs worked became the basis for the discovery of new drugs such as the selective serotonin reuptake inhibitors (SSRIs).

History and Discovery

In 1957, Roland Kuhn, a Swiss psychiatrist, investigated the clinical effects of imipramine in human subjects in part to determine whether its sedative properties might be useful (Kuhn 1958, 1970). He found that although imipramine was not useful in calming agitated patients, the drug did appear to ameliorate symptoms in depressed patients.

After imipramine was introduced, several other antidepressant compounds were developed and marketed. These compounds had a basic tricyclic or tetracyclic structure and shared many of the secondary effects for which the tricyclics came to be known.

Structure–Activity Relations

Tricyclic and tetracyclic compounds are categorized on the basis of their chemical structure (Figure 9–1). The tricyclics have a central three-ring structure, hence the name. The tertiary-amine tricyclics, such as amitriptyline and imipramine, have two methyl groups at the end of the side chain. These compounds can be demethylated to secondary amines, such as desipramine and nortriptyline. The tetracyclic compound maprotiline has a four-ring central structure. Five tertiary amines have been marketed in the United States—amitriptyline, clomipramine, doxepin, imipramine, and trimipramine. The three secondary-amine compounds are desipramine, nortriptyline, and protriptyline. All of these compounds, in addition to amoxapine and maprotiline, have been approved for use in major depressive disorder with the exception of clomipramine, which in the United States is approved for use only in obsessive-compulsive disorder (OCD).

FIGURE 9–1. Chemical structures of tricyclic and tetracyclic antidepressants.

The nature of the side chain appears to be important for the tricyclics’ function. The tertiary tricyclic agents—amitriptyline, imipramine, and clomipramine—are more potent in blocking the serotonin transporter. The secondary tricyclics are much more potent in blocking the norepinephrine transporter (Table 9–1) (Bolden-Watson and Richelson 1993; Tatsumi et al. 1997).

TABLE 9–1. Affinity of tricyclics and tetracyclics for neurotransmitter transporters and specific receptors (expressed as equilibrium dissociation constants)
	Potency uptake blockade			Receptor binding affinity
Drug	5-HT	NE	DA	α₁	α₂	H₁	M₁	5-HT_1A	5-HT₂
Amitriptyline	4.3	35	3,250	27	940	1.1	18	450	18
Amoxapine	58.0	16	4,310	50	2,600	25	1,000	220	1.0
Clomipramine	0.28	38	2,190	38	3,200	31	37	7,000	27
Desipramine	17.6	0.83	3,190	130	7,200	110	198	6,400	350
Doxepin	68.0	29.5	12,100	24	1,100	0.24	80	276	27
Imipramine	1.4	37	8,500	90	3,200	11	90	5,800	150
Maprotiline	5,800.0	11.1	1,000	90	9,400	2	570	12,000	120
Nortriptyline	18.0	4.37	1,140	60	2,500	10	150	294	41
Protriptyline	19.6	1.41	2,100	130	6,600	25	25	3,800	67
Trimipramine	149.0	2,450	3,780	24	680	0.27	58	8,400	32
Reference
Pentolamine				15
Yohimbine					1.6
D-Chlorpheniramine						15
Atropine							2.4
Serotonin								0.72
Ketanserin									2.5
Note. Affinity and potency=equilibrium dissociation constants in molarity. α₁=α₁-adrenergic; α₂=α₂-adrenergic; DA=dopamine; 5-HT=serotonin; 5-HT_1A=serotonin_1A; 5-HT₂=serotonin₂; H₁=histamine₁; M₁=muscarinic₁; NE=norepinephrine. Source. Potency uptake data adapted from Tatsumi et al. 1997. Receptor affinity data adapted from Richelson and Nelson 1984.

The structure of amoxapine differs from the structures of the other tricyclics. With a central three-ring structure and a side chain unlike those of the tricyclics, amoxapine is structurally closer to the antipsychotic loxapine, from which it is derived. Similar to the secondary tricyclics, it is a potent norepinephrine reuptake inhibitor. Unlike all of the other compounds in this group, amoxapine, and particularly its metabolite 7-hydroxyamoxapine, blocks postsynaptic dopamine receptors (Coupet et al. 1979). As a result, it is the only compound in the group that has antipsychotic activity in addition to antidepressant effects.

Maprotiline also differs from the others in this group. Although maprotiline is tetracyclic, its side chain is identical to that in desipramine, nortriptyline, and protriptyline. As would be predicted from this similarity, maprotiline is most potent in blocking the norepinephrine transporter (Randrup and Braestrup 1977).

Pharmacological Profile

Reuptake Blockade

Early in the history of the tricyclic and tetracyclic antidepressants, the ability of these compounds to block the transporter site for norepinephrine was described (Axelrod et al. 1961) (see Table 9–1). The tertiary amines have greater affinity for the serotonin transporter, whereas the secondary amines are relatively more potent at the norepinephrine transporter. During the administration of amitriptyline, imipramine, or clomipramine, these tertiary amines are demethylated to secondary amines; thus, both serotonergic and noradrenergic effects occur. In addition, because dopamine is inactivated by norepinephrine transporters in the frontal cortex (Bymaster et al. 2002), norepinephrine reuptake inhibitors would be expected to increase dopamine concentrations in that region.

Receptor Sensitivity Changes

The initial reuptake blockade described above is followed by a specific sequence of events (Blier et al. 1987; Charney et al. 1991; Tremblay and Blier 2006). Because the tertiary tricyclic compounds inhibit the uptake of serotonin, the levels of serotonin rise. As the result of inhibitory feedback from the presynaptic somatodendritic serotonin_1A (5-HT_1A) autoreceptor, the firing rate of the presynaptic serotonin neuron falls, and concentrations of 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of serotonin, decline rapidly. Over a 10- to 14-day period, the presynaptic autoreceptor is desensitized, and when this occurs, the tonic firing rate returns to its pretreatment rate. With both a normal firing rate and reuptake blockade, serotonin transmission is enhanced. The tricyclic agents also sensitize or upregulate postsynaptic 5-HT_1A receptors (de Montigny and Aghajanian 1978). These changes further enhance the effects of serotonin.

The tricyclics also downregulate the 5-HT₂ receptors (; Peroutka and Snyder 1980). In preclinical experiments, when the 5-HT₂ receptor was blocked by an antagonist, the effects of serotonin were enhanced (Lakoski and Aghajanian 1985; Marek et al. 2003). Some of the tricyclics—particularly amoxapine and doxepin, and to some extent amitriptyline—have 5-HT₂ antagonist properties relatively comparable to their reuptake potency (see Table 9–1) (Tatsumi et al. 1997).

The sequence of events with chronic dosing in the noradrenergic system is more complicated (Tremblay and Blier 2006). As in the serotonergic system, reuptake inhibition results in a rapid decline in norepinephrine turnover, as reflected by a drop in concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG), a metabolite of norepinephrine, and attenuation of the firing rate of the noradrenergic neuron. This effect appears to be mediated by the presynaptic somatodendritic α₂-adrenergic autoreceptor, which provides inhibitory feedback to the presynaptic neuron. In contrast to the firing rate of serotonergic neurons, the firing rate of noradrenergic neurons remains inhibited with chronic treatment (Szabo and Blier 2001), suggesting that somatodendritic α₂ receptors do not desensitize. Norepinephrine concentrations do increase at postsynaptic sites such as the hippocampus and frontal cortex. This may indicate desensitization of terminal α₂ autoreceptors.

With chronic treatment, the postsynaptic β-adrenergic receptor is downregulated, or decreased in density (Sulser et al. 1978). Current evidence suggests that β-adrenergic receptor downregulation is likely a compensatory change. Overall, chronic administration of a norepinephrine reuptake inhibitor appears to override the downregulation of the postsynaptic β-receptor, resulting in enhanced noradrenergic transmission. This effect manifests as enhanced formation of the second messenger cyclic adenosine monophosphate (cAMP) (Duman et al. 1997) and is reflected clinically by a persistent increase in heart rate (Roose et al. 1998; Rosenstein and Nelson 1991).

Secondary Effects

The tricyclic and tetracyclic compounds have a variety of additional actions mediated by other receptors (Cusack et al. 1994; Richelson and Nelson 1984) (see Table 9–1). For example, these compounds block muscarinic receptors, producing anticholinergic effects. Although these anticholinergic effects have generally been thought to mediate the adverse effects of tricyclics and tetracyclics, a double-blind randomized crossover study in 19 subjects with major depressive disorder found that the anticholinergic drug scopolamine had a beneficial effect on depressive and anxious symptoms (Furey and Drevets 2006). Consistent with this finding, donepezil, a cholinergic drug (a cholinesterase inhibitor), when given as an adjunct to an SSRI, increased the risk of depression relapse in older adults (Reynolds et al. 2011). The tricyclics also block histamine₁ (H₁) receptors and α₁- and α₂-adrenergic receptors, resulting in a variety of other effects (as discussed in the next section). Tricyclics act on voltage-gated sodium channels, which explains their adverse cardiac effects; however, these same actions may contribute to the beneficial effects of tricyclics on pain (Liang et al. 2014; Priest and Kaczorowski 2007). The potency of secondary effects of the tricyclics and tetracyclics varies considerably. Among the tricyclics, amitriptyline is the most anticholinergic and desipramine the least anticholinergic. Doxepin is the most potent H₁ antagonist among the tricyclics, but mirtazapine is even more potent. The consequences of these secondary effects are discussed below.

Pharmacokinetics and Disposition

Absorption

Absorption of the tricyclic and tetracyclic drugs occurs in the small intestine and is rapid and reasonably complete. Peak levels are reached within 2–8 hours following ingestion. Exceptions include protriptyline (peak levels reached between 6 and 12 hours after ingestion) and maprotiline (peak levels not reached until 8 hours or longer). Although peak levels may have implications for side effects, peak levels are relatively unimportant with respect to efficacy because the antidepressant action of these drugs occurs over several weeks.

Volume of Distribution

The tricyclic and tetracyclic compounds are basic lipophilic amines and are concentrated in a variety of tissues throughout the body. As a result, they have a high volume of distribution. For example, concentrations of these drugs in cardiac tissue exceed concentrations in plasma.

Plasma Protein Binding

The tricyclic and tetracyclic compounds are extensively bound to plasma proteins (e.g., 90% or greater) because of their lipid solubility. Exceptions are the hydroxy metabolites, which have lower plasma protein binding than the parent compounds.

First-Pass Metabolism

Following absorption, the tricyclics are taken up in the circulation but pass first through the liver, and metabolism of the drug begins—the so-called first-pass effect. As a result, the amount of the compound that enters the systemic circulation is reduced.

Hepatic Metabolism

Hepatic metabolism is the principal method of clearance for the tricyclic and tetracyclic compounds. Only a small portion of drug is eliminated by the kidneys. Rates of hepatic metabolism vary widely from person to person, resulting in dramatic differences in steady-state plasma concentrations. Elimination half-lives for most of the tricyclic and tetracyclic compounds average about 24 hours or longer; thus, the drugs can be given once a day (Table 9–2). Amoxapine has a shorter half-life than the other tricyclics and is an exception.

TABLE 9–2. Dosage, clearance, and apparent therapeutic plasma concentrations of tricyclics and tetracyclics
	Plasma		Therapeutic
Drug	Half-life (hours)	Clearance (L/hour)	Dosage range (mg/day)	Plasma level (ng/mL)
Tertiary tricyclics
Amitriptyline	5–45	20–70	150–300
Clomipramine	15–60	20–120	150–300	>150^a
Doxepin	10–25	40–60	150–300
Imipramine	5–30	30–100	150–300	>200^a
Trimipramine	15–40	40–105
Secondary tricyclics
Desipramine	10–30	80–170	75–300	>125
Nortriptyline	20–55	15–80	50–150	50–150
Protriptyline	55–200	5–25	15–60
Tetracyclics
Amoxapine	5–10	225–275	150–300
Maprotiline	25–50	15–35	100–225
^aTotal concentration of the parent compound and the desmethyl metabolite. Source. Adapted from Nelson JC: “Tricyclic and Tetracyclic Drugs,” in Comprehensive Textbook of Psychiatry/VII, 7th Edition. Edited by Kaplan HI, Sadock BJ. Baltimore, MD, Lippincott Williams & Wilkins, 2000, p. 2494. Copyright 2000, Lippincott Williams & Wilkins. Used with permission.

Hepatic metabolism of the tricyclics and tetracyclics occurs along two principal metabolic pathways. Demethylation of the side chain converts the tertiary amines to secondary amines. The other pathway in hepatic metabolism is hydroxylation of the ring structure, which produces hydroxy metabolites. In some cases, the levels of the metabolite are substantial. The concentration of 10-hydroxynortriptyline usually exceeds that of the parent compound (Bertilsson et al. 1979). Usually 2-hydroxydesipramine is present at levels approximately 40%–50% of those of the parent compound, but these ratios are quite variable and depend on the rate of hydroxylation (Bock et al. 1983; Potter et al. 1979). Hydroxyimipramine and hydroxyamitriptyline are present at very low concentrations and are clinically unimportant. The hydroxy metabolites are then conjugated and excreted. The conjugated metabolites are not active.

Hydroxynortriptyline and hydroxydesipramine both block the norepinephrine transporter (Bertilsson et al. 1979; Potter et al. 1979). Both have antidepressant activity (Nelson et al. 1988b; Nordin et al. 1987). The norepinephrine reuptake potency of hydroxydesipramine is comparable to that of the parent compound. There are two isomers of hydroxynortriptyline, E- and Z-10-hydroxynortriptyline. E-10-hydroxynortriptyline is present at levels four times higher than those of the Z isomer and is about 50% as potent as nortriptyline in blocking norepinephrine uptake.

The principal metabolic pathway for amoxapine is hydroxylation, during which 7-hydroxyamoxapine and 8-hydroxyamoxapine are produced (Coupet et al. 1979). These compounds differ: whereas 7-hydroxyamoxapine has high-potency antipsychotic properties but a short half-life, 8-hydroxyamoxapine is metabolized more slowly and appears to contribute to the drug’s antidepressant action.

The CYP2D6 pathway appears to be responsible for hydroxylation of desipramine and nortriptyline (Brøsen et al. 1991). In fact, desipramine is considered to be the prototypic substrate for CYP2D6 because it has no other major metabolic pathways. Demethylation of the tertiary-amine compounds involves a number of CYP isoenzymes, including 1A2, 3A4, and 2C19. These hepatic isoenzymes are under the control of specific genes, and gene loci for several of these isoenzymes, including CYP2D6, have been identified. Approximately 5%–10% of Caucasians are homozygous for the recessive autosomal 2D6 trait, resulting in deficient hydroxylation of desipramine and nortriptyline (Brøsen et al. 1985; Evans et al. 1980). These individuals are termed poor metabolizers, whereas those with adequate 2D6 enzyme are referred to as extensive metabolizers. Among individuals of Asian descent, approximately 50% carry the CYP2D6*10 allele, which is associated with intermediate metabolism of 2D6 substrates (Ji et al. 2002). For example, the elimination half-life of nortriptyline is doubled in individuals homozygous for this allele (Yue et al. 1998). Approximately 20% of Asian individuals have a genetic polymorphism resulting in deficient CYP2C19 metabolism.

The variability in plasma concentrations that results from these metabolic differences is substantial. For example, in a sample of 83 Caucasian inpatients who were given a fixed dose (2.5 mg/kg) of desipramine, we observed steady-state plasma concentrations ranging from 20 ng/mL to 934 ng/mL (Nelson 1984).

P-Glycoprotein and the Blood–Brain Barrier

P-glycoprotein (P-gp) is located at the blood–brain barrier and acts as an efflux pump. Its function is to protect the organism from exogenous compounds. It is hypothesized that by limiting uptake of antidepressants into the central nervous system (CNS), P-gp contributes to medication resistance. Most tricyclics are substrates of P-gp (Akamine et al. 2012; O’Brien et al. 2012). The effectiveness of P-gp is reduced in the presence of P-gp inhibitors (e.g., verapamil and quinidine), and these agents would be expected to raise CNS concentrations of P-gp substrates (Weiss et al. 2003); however, the utility of adjunctive treatment with a P-gp inhibitor to improve outcomes has not been demonstrated.

P-gp is encoded by the ABCB1 gene. Polymorphisms of the ABCB1 gene decrease the efficiency of P-gp and should result in higher CNS concentrations of P-gp substrates. The first study to examine the contribution of the ABCB1 gene to antidepressant effectiveness found that remission of depression was more likely if ABCB1 polymorphisms were present and the antidepressant was a P-gp substrate, but found no association if the antidepressant was not a P-gp substrate (Uhr et al. 2008). Yet a recent review and meta-analysis of the association of ABCB1 variants and outcome reported considerable variability in the findings of 16 studies conducted, both in terms of whether any association was found and in terms of which genetic variant was associated with greater response (Breitenstein et al. 2015). Furthermore, the two largest studies included in this meta-analysis (GENDEP [Genome-Based Therapeutic Drugs for Depression] and STAR*D [Sequenced Treatment Alternatives to Relieve Depression]) found that none of the ABCB1 variants was associated with response to P-gp substrate antidepressants. The lack of association in the largest studies suggests limited applicability of the ABCB1 genotype as a predictor of response in depression.

Steady-State Concentrations

Steady state is the point on a fixed dose at which plasma concentrations of the drug reach a plateau. Steady state is achieved after five half-lives. If blood level monitoring is employed, a sample is drawn immediately before the next dose is scheduled to be given, usually in the morning, after the patient’s level has reached steady state. Steady-state drug concentrations should remain relatively stable as long as the dosage is constant, the patient is adherent to the medication regimen, and no interactive drugs are added. If only one sample is drawn, the clinician should bear in mind that even if the laboratory error is low, there will be moderate biological variability (±10%–15%). Single blood level samples are better viewed as estimates than as precise measures.

When the drug concentration is measured, the total of both the free and bound drug is reported. Drug concentrations in the cerebrospinal fluid are proportional to the free levels. The free concentration is dependent on dose and hepatic clearance but is not affected by plasma protein binding (Greenblatt et al. 1998). Factors that affect plasma proteins—malnutrition, inflammation—may lead to changes in the bound fraction, but the absolute free concentration is unaffected.

Linear Kinetics

Most of the tricyclics have linear kinetics; that is, concentration increases in proportion to dose within the therapeutic range. There are exceptions. Desipramine, for example, has nonlinear kinetics at the usual dosage range (Nelson and Jatlow 1987). In cases of overdose, nonlinear changes are more likely to occur, and the clinician cannot assume that usual rates of drug elimination will be maintained.

Effects of Aging

Changes in the pharmacodynamics and pharmacokinetics of medications occur with aging, yet some are relatively unimportant (Greenblatt et al. 1998). The ratio of fat to lean body mass increases, and cardiac output and hepatic blood flow decrease. There may be further changes associated with medical illness. But the clinical importance of these changes is usually relatively minor because of the dramatic variability of hepatic metabolism. The activity of the CYP3A4 pathway does slow with age (von Moltke et al. 1995), and concentrations of the tertiary amines are increased somewhat in older individuals (Abernethy et al. 1985). Alternatively, most studies of nortriptyline (Katz et al. 1989; Young et al. 1984) and desipramine (Abernethy et al. 1985; Nelson et al. 1985, 1995) indicate that ratios of blood level to dosage of these drugs are relatively unaffected by aging, suggesting that the 2D6 isoenzyme is not similarly affected. Renal clearance of the hydroxy metabolites does decrease with age (Nelson et al. 1988a; Young et al. 1984). As a result, concentrations of hydroxynortriptyline may be substantially elevated in older patients.

In children, the clearance of tricyclic compounds is increased. Half-lives of imipramine are shorter, and ratios of desmethylimipramine to imipramine are higher, consistent with more rapid metabolism (Geller 1991; Rapoport and Potter 1981). Alternatively, a study of desipramine in children found that the clearance of both desipramine and hydroxydesipramine was increased, so that hydroxy metabolite–parent compound ratios were not elevated (Wilens et al. 1992).

Relationship of Plasma Concentration to Clinical Action

Plasma Concentration and Response

Marked interindividual variability of tricyclic plasma concentrations was described by Hammer and Sjöqvist in 1967. This finding suggested that drug level monitoring might ensure that therapeutic blood levels are achieved and might help to avoid toxic levels. In carefully selected inpatients with endogenous or melancholic major depression, treatment with adequate levels of imipramine or desipramine resulted in robust response rates of about 85% (Glassman et al. 1977; Nelson et al. 1982). But similar relationships have proven difficult to demonstrate in depressed outpatients. In outpatients, drug–placebo differences are often small, and the effect of drug treatment is harder to detect. Depressed outpatients may be more heterogeneous and include individuals who are not responsive to any drug treatment. It is logical to conclude that blood level relationships determined in severely depressed inpatients might be used as a guide for treatment of outpatients, but this assumption has not been empirically validated.

A task force of the American Psychiatric Association (1985) that reviewed studies relating tricyclic plasma levels and response concluded that a relationship had been demonstrated for imipramine, desipramine, and nortriptyline (see Table 9–2). Data on the relationship between blood level and response in depression are limited or conflicting for the other tricyclic and tetracyclic compounds.

Plasma Concentration and Toxicity

Blood level monitoring may help to avoid toxicity. The risk of delirium is substantially increased at amitriptyline plasma concentrations above 450 ng/mL and is moderately increased at concentrations above 300 ng/mL (Livingston et al. 1983; Preskorn and Simpson 1982). But amitriptyline is the most anticholinergic tricyclic and is most likely to produce delirium. The risk of first-degree atrioventricular block is also increased at imipramine plasma concentrations greater than 350 ng/mL (Preskorn and Irwin 1982). The risk of seizures also increases at higher dosages and, presumably, higher blood levels, although a clear plasma level threshold for seizures has not been demonstrated. Following overdose, tricyclic blood levels greater than 1,000 ng/mL can be achieved, and the risks of delirium, stupor, cardiac abnormalities, and seizures are all substantially increased (Preskorn and Irwin 1982; Rudorfer and Young 1980; Spiker et al. 1975). The value of blood level monitoring for avoidance of serious adverse effects has been difficult to demonstrate; given that rates of serious toxicity are low, large samples would be required to demonstrate any increase in risk at higher blood levels.

If blood level monitoring is undertaken, the clinician should bear in mind that many factors—including laboratory variability, blood sampling errors, missed doses, and biological variability—can affect drug concentrations. For this reason, the clinician should not view the concentration reported as a precise measure. Yet because concentrations vary across such a wide range, it may be very helpful to know whether the level is low (e.g., 25–75 ng/mL), moderate (e.g., 100–300 ng/mL), or high (e.g., 300–1,000 ng/mL).

Prospective Dosing Techniques

The demonstrated relationship between timed drug concentrations after a single tricyclic dose and the steady-state level achieved suggests the possibility of using plasma levels obtained early in treatment to rapidly adjust the dose. A clinical study using desipramine found that treatment could be initiated at full dosage once the dosage needed to reach a therapeutic level was determined from a 24-hour blood level following a test dose (Nelson et al. 1987). However, the practical application of this method was limited. Most laboratories are not prepared to determine drug concentrations accurately at very low levels (as needed following a test dose) and are unable to report results quickly. A more practical and clinically feasible method is to start the drug at a low or moderate fixed dose, obtain a blood sample after 5–7 days on that dose, and then make further adjustments based on that level. There are exceptions. Elderly depressed patients often require gradual dosing in order to assess tolerance. In patients with panic attacks, lower starting doses are employed to avoid exacerbation of panic attacks.

Mechanism of Action

Early studies observed that the tricyclic agents blocked uptake of monoamines at the norepinephrine and serotonin transporters (Axelrod et al. 1961). This drug effect was quickly put forward as a possible mechanism of action. The observation that reserpine, which depletes presynaptic catecholamines, might induce depression in vulnerable individuals supported this hypothesis (F.K. Goodwin and Bunney 1971). Confirmation that norepinephrine and serotonin do in fact mediate the action of monoamine reuptake inhibitors was provided by subsequent challenge studies in depressed patients. For example, administration of a tryptophan-free diet rapidly depletes serotonin and causes relapse in depressed patients who have been successfully treated with a serotonin reuptake inhibitor but not a norepinephrine reuptake inhibitor (Delgado et al. 1990). Alternatively, administration of α-methyl-p-tyrosine (AMPT), which interrupts the synthesis of catecholamines, caused relapse in patients who were being successfully treated with noradrenergic agents but not those receiving serotonergic drugs (Delgado et al. 1993). These studies provide supporting evidence that serotonin and norepinephrine mediate antidepressant effects, but they do not necessarily imply that alterations in these neurotransmitter systems are central to the etiology of depression.

Subsequent research on the mechanism of action of the tricyclics and other antidepressant drugs has shifted to include consideration of factors affecting postsynaptic signal transduction (Manji et al. 1995). Such factors include coupling of G proteins to the adrenergic receptor or to adenylyl cyclase and the activity of membrane phospholipases and protein kinases. Other newer targets, including glucocorticoid receptors (Barden 1996), neurotrophic factors (Duman et al. 1997), and gene expression (Lesch and Manji 1992; Nibuya et al. 1996; Schwaninger et al. 1995), have been explored.

Indications and Efficacy

Major Depressive Disorder

The efficacy of the tricyclic and tetracyclic compounds in major depression is well established. The evidence for their effectiveness has been reviewed previously (Agency for Health Care Policy and Research 1993; Davis and Glassman 1989). Imipramine is the most extensively studied tricyclic antidepressant, in part because new drugs were often compared with it. In 30 of 44 placebo-controlled studies, imipramine was more effective than placebo. If data from these studies are combined, 65% of 1,334 patients completing treatment with imipramine were substantially improved, whereas 30% of those on placebo improved. Intention-to-treat response rates for placebo-controlled studies of imipramine in outpatients were 51% for imipramine and 30% for placebo (Agency for Health Care Policy and Research 1993). The other tricyclic and tetracyclic antidepressants appeared comparable to imipramine in efficacy.

The tricyclic compounds are also effective when used for maintenance treatment. Frank et al. (1990) found that imipramine, at full dosage, effectively maintained nearly 80% of the depressed patients for a 3-year period, compared with 10% of those on placebo. In this study, maintenance psychotherapy had an intermediate effect, with about 30% of the patients remaining well. In practice, clinicians may encounter patients with chronic depression, with residual symptoms, or with comorbid medical and psychiatric disorders. For such patients, the effects of maintenance treatment are less robust.

The U.S. Food and Drug Administration (FDA) has approved all of the tricyclic and tetracyclic compounds discussed in this chapter for the treatment of depression, with the exception of clomipramine. In Europe, clomipramine is also used for depression; in fact, it is regarded by many as the most potent antidepressant.

Depression With Melancholic Features (Severe Depression)

The efficacy of the tricyclic compounds appears to vary in different subtypes of depression. The early studies of tricyclic compounds were frequently conducted in hospitalized patients with severe or melancholic depression, and in these patients the tricyclics were found to be effective. In fact, the tricyclics may be especially effective in this group. Two studies of imipramine and desipramine found rates of response of about 85% in severely depressed hospitalized patients who did not have a history of treatment-resistant depression, did not have prominent personality disorder, received an adequate plasma concentration of the drug, and completed treatment (Glassman et al. 1977; Nelson et al. 1982).

When the SSRIs were introduced, it was suggested that they might be less effective than the tricyclic antidepressants in treating severe or melancholic depression. However, in a large meta-analysis of more than 100 comparison studies, Anderson (2000) found that tricyclic antidepressants and SSRIs had comparable efficacy. In a separate meta-analysis of 25 inpatient studies (Anderson 1998), the advantage of the tricyclics appeared limited to those with dual action, namely amitriptyline and clomipramine. In outpatient populations, the designation of melancholia does not appear to predict an advantage for tricyclic antidepressants versus SSRIs (Anderson and Tomenson 1994; Montgomery 1989).

Depression With Anxious Distress

The use of tricyclics in anxious depression—or depression with anxious distress in DSM-5 (American Psychiatric Association 2013) terminology—has been frequently studied. Doxepin, amoxapine, and maprotiline have received FDA approval for use in patients with depression and symptoms of anxiety. Direct comparison studies, however, have found little indication that one tricyclic is better than another for treatment of anxious depression. Compared with depressed patients who are not prominently anxious, depressed patients who are anxious may respond less well to amitriptyline (Kupfer and Spiker 1981), imipramine (Roose et al. 1986), and desipramine (Nelson et al. 1994). Yet these drugs are still more effective than placebo in anxious depressed patients, and it is not established that another drug class is more effective in these patients.

Depression With Atypical Features

A series of studies examined the efficacy of imipramine in depressed patients with atypical features (Liebowitz et al. 1984, 1988). Imipramine was more effective than placebo but significantly less effective than the monoamine oxidase inhibitor (MAOI) phenelzine. Other investigators have reported the value of switching from a tricyclic to an MAOI in tricyclic-refractory depressed patients with atypical features (McGrath et al. 1987; Thase et al. 1992). In fact, the validity and utility of atypical depression were in large part supported by this observed differential response.

Depression With Psychotic Features

In 1975, Glassman et al. observed that imipramine was less effective in patients with major depression who had delusions. Subsequently, Chan et al. (1987) reviewed several studies involving more than 1,000 patients and found that antidepressants—usually tricyclics—given alone were effective in approximately two-thirds of depressed patients without psychosis but in only about one-third of those with psychotic features. Several open studies reviewed elsewhere (Nelson 1987) and one prospective study (Spiker et al. 1985) found that the tricyclics, when combined with an antipsychotic, are effective in psychotic depression.

Anton and Burch (1990) suggested that because of its antipsychotic effects, amoxapine might be effective for psychotic depression. In a double-blind study, these researchers demonstrated that amoxapine was comparable in efficacy to the combination of perphenazine and amitriptyline in treating psychotic depression (Anton and Burch 1990).

Bipolar Depression

Forty years ago, it was suggested that the MAOI antidepressants might be more effective than the tricyclics in treating bipolar depression (Himmelhoch et al. 1972). Later, Himmelhoch et al. (1991) demonstrated in a double-blind study that tranylcypromine was more effective than imipramine for bipolar depression. Because tricyclics are more likely than other agents to induce mania (Wehr and Goodwin 1987), they are not recommended for monotherapy of bipolar depression.

Persistent Depressive Disorder (Dysthymia)

The new DSM-5 diagnostic category persistent depressive disorder (dysthymia) includes both chronic major depressive disorder and dysthymia. Imipramine appears to be effective in treating chronic depression and to be relatively comparable to sertraline in efficacy (Keller et al. 1998; Kocsis et al. 1988). Imipramine and desipramine have both been studied in controlled trials in dysthymia. Imipramine was found to be more effective than placebo for acute treatment (Thase et al. 1996), and desipramine was more effective than placebo for maintenance treatment (Miller et al. 2001) of dysthymia.

Late-Life Depression

Gerson et al. (1988) reviewed studies of tricyclic antidepressants in older patients reported prior to 1986. They found 13 placebo-controlled trials but noted several methodological problems. Although tricyclics were effective, overall response rates in older patients appeared to be lower than rates in nonelderly patients (Agency for Health Care Policy and Research 1993). Katz et al. (1990) performed one of the first placebo-controlled trials of nortriptyline in the treatment of patients older than 80 years living in a residential care facility. Nortriptyline was more effective than placebo. The doses employed and levels achieved were similar to those in younger subjects. This study remains the only study to date showing an advantage for an antidepressant over placebo in depressed nursing home patients.

Depression in Children

In children and adolescents, the tricyclic antidepressants have not demonstrated superiority over placebo (Ryan 1992).

Panic Disorder

Although none of the tricyclic or tetracyclic drugs is approved for use in panic disorder, imipramine was the first drug described for use in this disorder (Klein 1964). The efficacy of both tertiary and secondary tricyclics has been demonstrated in controlled trials (Jobson et al. 1978; Munjack et al. 1988; Zitrin et al. 1980). In treating this disorder, the drug is initiated at a low dose to avoid exacerbation of panic symptoms.

Obsessive-Compulsive Disorder

Unlike depression, which responds to a variety of antidepressant agents, OCD appears to require treatment with a serotonergic agent. Clomipramine, the most serotonergic of the tricyclics, is approved by the FDA for use in OCD, and its efficacy in this disorder is well established (Greist et al. 1995). Studies comparing its effectiveness with that of noradrenergic agents such as desipramine found that clomipramine was substantially superior (Leonard et al. 1989). Although the SSRIs are effective in treating OCD, there is a suggestion that clomipramine may be superior (Greist et al. 1995). Whether this suggested superiority is due to the dual mechanism of clomipramine or to other factors is unclear.

Attention-Deficit/Hyperactivity Disorder

The efficacy of the stimulant drugs in treating attention-deficit/hyperactivity disorder (ADHD) is well established. The tricyclics, especially desipramine, also appear to be of value. In one study, desipramine, given at dosages greater than 4 mg/kg for 3–4 weeks, was effective in two-thirds of the children, whereas placebo was effective in only 10% (Biederman et al. 1989). Desipramine was also found to be more effective than placebo in adults with ADHD (Wilens et al. 1996). One of the advantages of desipramine is its low potential for abuse. Unfortunately, five cases of sudden death were reported in the early 1990s in children being treated with desipramine (Riddle et al. 1991, 1993). All were under the age of 12 years. As a result, desipramine is contraindicated in children younger than 12 years (discussed in greater detail below; see section “Side Effects and Toxicology”). Given that tricyclics as a group share the same adverse cardiac effects, there is reason to be concerned that other tricyclics might also have safety issues in young children (see also Chapter 55, “Treatment of Child and Adolescent Disorders”).

Pain Syndromes

The tricyclics and the tetracyclic maprotiline have been widely used in various chronic pain syndromes. In a review of the literature, O’Malley et al. (1999) identified 56 controlled studies involving tricyclic antidepressant therapy for various pain syndromes, including headache (21 studies), fibromyalgia (18 studies), functional gastrointestinal syndromes (11 studies), idiopathic pain (8 studies), and tinnitus (2 studies); and Salerno et al. (2002) identified 7 more placebo-controlled trials of tricyclics or maprotiline used for chronic back pain. These agents were quite effective; the mean effect size (0.87) and the drug–placebo difference in response rates (32%) in the pain trials were more robust than those usually observed in placebo-controlled studies in depression. The analgesic effects of these compounds were not simply the result of their antidepressant effects.

The mechanism of these agents’ analgesic effects appears to differ from that of their antidepressant effects. The antinociceptive actions of the antidepressants result from actions on descending norepinephrine and serotonin pathways in the spinal cord (Yoshimura and Furue 2006). In animals, the antinociceptive effects of norepinephrine reuptake inhibitors and combined norepinephrine–serotonin reuptake inhibitors appear to be more potent than those of SSRIs (Mochizucki 2004). In humans, there is some evidence that the combined-action agents amitriptyline and clomipramine are more effective than the SSRI fluoxetine (Max et al. 1992) or the norepinephrine-selective agents maprotiline (Eberhard et al. 1988) and nortriptyline (Panerai et al. 1990). In humans, antidepressant dosing and timing of effects for pain differ from those for depression. For example, usual dosages of amitriptyline required for pain management (≤75 mg/day) are lower than those required to treat depression (15–300 mg/day), and response occurs more quickly, usually within the first 1 or 2 weeks.

Other Indications

Imipramine has been used for treatment of nocturnal enuresis in children, with FDA approval, and controlled trials indicate efficacy (Rapoport et al. 1980). The dose of imipramine is usually 25–50 mg at bedtime. Amitriptyline and nortriptyline also appear to be useful for this indication, although they are not FDA approved for use in the disorder. The mechanism of action is unclear but may in part be anticholinergic. Given the serious cardiac risks attached to desipramine’s use in children younger than 12 years (discussed in earlier subsection “Attention-Deficit/Hyperactivity Disorder”), concerns have been raised regarding whether tricyclics other than desipramine might also pose safety risks in this population. However, the low doses used in imipramine treatment of pediatric nocturnal enuresis may reduce this risk.

Tricyclic antidepressant drugs have been extensively studied in patients with schizophrenia. However, in the absence of a major depressive episode, these agents appear to be of limited value (Siris et al. 1978).

The more sedating tricyclics have been used to treat insomnia, and doxepin (as Silenor) is FDA approved for this indication. Because of its antihistaminic effects, doxepin has also been used for pruritis and is FDA indicated (as Zonalon) for short-term management of moderate pruritus in atopic dermatitis and lichen simplex chronicus.

Side Effects and Toxicology

Distinguishing side effects during tricyclic treatment from the somatic symptoms of depression can be complicated. During treatment, patients may attribute somatic symptoms to drug side effects even if the symptoms were preexisting. One study found that the strongest predictor of overall somatic symptom severity was the severity of the depression at the time of assessment (Nelson et al. 1984).

Another general factor contributing to side effects is the patient’s vulnerability. For example, one of the best predictors of orthostatic hypotension during treatment is the presence of orthostatic hypotension prior to treatment (Glassman et al. 1979). Seizures are most likely in a patient with a history of seizures (Rosenstein et al. 1993). Cardiac conduction problems are most likely to occur in patients with preexisting conduction delay (Roose et al. 1987a).

Antidepressant drugs do have effects on a variety of organs and can produce adverse effects. The in vitro potency or affinity of antidepressant compounds for various receptor sites (see Table 9–1) is one factor determining the likelihood that specific side effects will be produced. A related issue is how the in vitro potency of a secondary effect relates to the potency of the primary action of the drug. If the secondary effect is more potent, it will occur at concentrations below the therapeutic level of the drug. For example, orthostatic hypotension often occurs at plasma concentrations below the usual therapeutic threshold. Alternatively, the proarrhythmic and proconvulsant effects of the tricyclic antidepressants become more pronounced at elevated blood levels or those encountered in overdose.

Central Nervous System Effects

The principal action of the tricyclic and tetracyclic agents in the CNS is to reduce the symptoms of depression. Nondepressed subjects given imipramine may feel sleepy, quieter, light-headed, clumsy, and tired. These effects are generally unpleasant (DiMascio et al. 1964).

The anticholinergic and antihistaminic effects of the tricyclics and tetracyclics can produce confusion or delirium. The incidence of delirium is dose dependent, with delirium risk increasing at blood levels above 300 ng/mL (Livingston et al. 1983; Preskorn and Simpson 1982). The risk of delirium appears to be higher with the more anticholinergic agents, such as amitriptyline. Patients with concurrent dementia are particularly vulnerable to the development of delirium, and the more anticholinergic tricyclics should be avoided in such patients. Intramuscular or intravenous physostigmine can be used to reverse or reduce the symptoms of delirium, but physostigmine’s short duration of action makes its continued use difficult.

Seizures can occur with all of the tricyclic and tetracyclic agents and are dosage and blood level related (Rosenstein et al. 1993). For clomipramine, the risk of seizures is reported to be 0.5% at dosages up to 250 mg/day. At clomipramine dosages above 250 mg/day, the seizure risk increases to 1.67% (clomipramine new drug application data on file with the FDA). The seizure risk for such as imipramine and amitriptyline were not well established at the time of marketing. Two of the largest studies found that seizure risk varied from 0 to 0.6% or 0.7% for various tricyclic compounds and were clearly dose related (Jick et al. 1983; Peck et al. 1983). The risk of seizures is substantially increased following overdose (Spiker et al. 1975). The cumulative data to date suggest that amoxapine, clomipramine, and maprotiline present the highest seizure risk among this group of agents (Johannessen Landmark et al. 2016). The risk of convulsions is increased in patients with predisposing factors such as a history of seizures, the presence of brain injury, or the use of antipsychotics. The mechanism by which tricyclics produce seizures is not well understood.

A fine, rapid tremor can occur with use of tricyclic agents. Because tremors are dose dependent, tend to occur at higher blood levels, and are not typical depressive symptoms, development of a tremor may be a clinical indicator of an elevated blood level (Nelson et al. 1984).

Because the 7-hydroxy metabolite of amoxapine has antipsychotic properties, administration of amoxapine carries the potential risk of neuroleptic malignant syndrome and tardive dyskinesia. Although these adverse events are rare, the seriousness of the risk and the availability of alternatives suggest that use of amoxapine should be reserved for patients whose clinical condition warrants treatment with an agent possessing antipsychotic properties.

Anticholinergic Effects

The tricyclics block muscarinic receptors and can cause a variety of anticholinergic side effects, such as dry mouth, constipation, blurred vision, and urinary hesitancy. These effects can precipitate an ocular crisis in patients with narrow-angle glaucoma. The tricyclic and tetracyclic compounds vary substantially in their muscarinic potency (see Table 9–1). Amitriptyline is the most potent, and desipramine is the least anticholinergic. Amoxapine and maprotiline also have minimal anticholinergic effects. Anticholinergic effects can contribute to tachycardia, but tachycardia also occurs as a result of stimulation of β-adrenergic receptors in the heart. Thus, tachycardia also occurs in patients receiving desipramine, which is minimally anticholinergic (Rosenstein and Nelson 1991).

Although anticholinergic effects are annoying, they are usually not serious. They can, however, become severe. An ocular crisis in patients with narrow-angle glaucoma is an acute condition associated with severe pain. Urinary retention can be associated with stretch injuries to the bladder. Constipation can progress to severe obstipation. (Paralytic ileus has been described but is rare.) In these conditions, medication must be discontinued and appropriate supportive measures instituted. Elderly patients are at greatest risk for severe adverse consequences. The incidence of severe anticholinergic adverse reactions is increased by concomitant administration of other anticholinergic agents. Use of a tricyclic with weak anticholinergic properties, such as nortriptyline or desipramine, can help to reduce the likelihood of these problems.

Anticholinergic side effects may benefit from other interventions. Bethanechol (Urecholine) at a dosage of 25 mg three or four times a day may be helpful in patients with urinary hesitancy. The regular use of stool softeners helps to manage constipation. Patients with narrow-angle glaucoma who are receiving pilocarpine eye drops regularly can be treated with a tricyclic, as can those who have had an iridectomy. Tricyclic agents do not affect patients with chronic open-angle glaucoma.

Antihistaminic Effects

Several of the tricyclic compounds and maprotiline have clinically significant antihistaminic effects. Doxepin, the most potent H₁ receptor antagonist among the tricyclics, is more potent than diphenhydramine but less potent than mirtazapine. Central H₁ receptor blockade can contribute to sedation and delirium and also appears to be related to the increased appetite and associated weight gain that patients may develop with chronic treatment. Because of their sedating effects, the tricyclic antidepressants, especially amitriptyline, have been used as hypnotics. Given their cardiac effects and lethality in overdose, this practice should be discouraged.

Cardiovascular Effects

Orthostatic hypotension is one of the most common reasons for discontinuation of tricyclic antidepressant treatment (Glassman et al. 1979). It can occur with all of the tricyclics but appears to be less pronounced with nortriptyline (Roose et al. 1981; Thayssen et al. 1981). The α₁-adrenergic blockade associated with the tricyclics contributes to orthostatic hypotension; however, it is the postural reflex that is primarily affected. Resting supine blood pressure may be unaffected or can even be elevated (Walsh et al. 1992). Orthostatic hypotension is most likely to occur or is most severe in patients who have preexisting orthostatic hypotension (Glassman et al. 1979). It is also aggravated by concurrent antihypertensive medications, especially volume-depleting diuretic agents. The elderly are more likely to have preexisting hypotension and are also more vulnerable to the consequences of orthostatic hypotension, such as falls and hip fractures.

Orthostatic hypotension often occurs at low medication blood levels. Gradual dosage adjustment may allow accommodation to the subjective experience of light-headedness, but the actual orthostatic blood pressure changes do not accommodate within a reasonable period of time (e.g., 4 weeks) (Roose et al. 1998). As a consequence, patients who experience serious symptomatic orthostatic hypotension may not be treatable with a tricyclic antidepressant. Fludrocortisone (Florinef) has been used to raise blood pressure, but in this author’s experience it is not very effective. If patients are receiving antihypertensives, it may be possible and helpful to reduce the dosage of these agents.

Desipramine has been reported to raise supine blood pressure in young women (ages 18–45 years), although it is not clear that this effect is limited to that age group (Walsh et al. 1992). The elevation in blood pressure may be similar to that reported for venlafaxine.

Tachycardia occurs with all of the tricyclics, not just the more anticholinergic agents. Both supine and postural pulse changes can occur, and the standing pulse can be markedly elevated. A study of nortriptyline, dosed to a therapeutic plasma concentration, found a mean pulse increase of 11% (8 beats per minute) (Roose et al. 1998). Patients do not accommodate to the pulse rise, which can persist for months. Tachycardia is more prominent in young patients, who appear to be more sensitive to sympathomimetic effects, and is one of the most common reasons for drug discontinuation in adolescents. A persistent pulse rise, however, increases cardiac work and may be clinically significant in patients with ischemic heart disease.

The effect of tricyclic antidepressants on cardiac conduction has been a subject of great interest. Cardiac arrhythmia is the principal cause of death following tricyclic overdose (Spiker et al. 1975). Apparently, through inhibition of sodium/potassium (Na⁺/K⁺) adenosine triphosphatase (ATPase), the tricyclics stabilize electrically excitable membranes and delay conduction, particularly His ventricular conduction. Consequently, the tricyclics have type I antiarrhythmic qualities or quinidine-like effects.

At therapeutic blood levels, the tricyclics can have beneficial effects on ventricular excitability. In patients with preexisting conduction delay, however, the tricyclic antidepressants can cause heart block (Glassman and Bigger 1981; Roose et al. 1987b). A pretreatment QTc interval of 450 milliseconds or greater indicates that conduction is already delayed and that the patient is not a candidate for tricyclic antidepressant treatment. High drug plasma levels (e.g., imipramine plasma concentrations >350 ng/mL) increase the risk of first-degree atrioventricular heart block (Preskorn and Irwin 1982). The tricyclic antidepressants do not reduce cardiac contractility or cardiac output (Roose et al. 1987a).

Glassman et al. (1993), noting that the type I antiarrhythmic drugs routinely given following myocardial infarction actually increase the risk of sudden death, suggested that the tricyclics may pose similar risks. The risk of sudden death is also increased when heart rate variability is reduced, and the tricyclics reduce heart rate variability (Roose et al. 1998).

As mentioned earlier (see subsection “Attention-Deficit/Hyperactivity Disorder”), five cases of sudden death were reported in children younger than 12 years who were receiving desipramine (Riddle et al. 1991, 1993). It was suggested that the immature conduction system in some children might render them more vulnerable to the cardiac effects of desipramine. However, no cardiac abnormalities were observed in a study of 71 children with 24-hour cardiac monitoring (Biederman et al. 1993). These findings suggest that cardiac events in children are not dose dependent and that electrocardiogram monitoring is not likely to identify those at risk.

Hepatic Effects

Acute hepatitis has been associated with use of imipramine (Horst et al. 1980; Moskovitz et al. 1982; Weaver et al. 1977) or desipramine (Powell et al. 1968; Price et al. 1983). Mild increases in liver enzymes (less than three times normal) are not uncommon and usually can be monitored safely over a period of days or weeks. Enzyme changes do not appear to be related to drug concentrations (Price et al. 1984). Acute hepatitis is relatively uncommon but can occur. The etiology is not well established, but in some cases the condition appears to represent a hypersensitivity reaction. Tricyclic-induced acute hepatitis is characterized by very high enzyme levels (e.g., aspartate aminotransferase [AST] levels >800), which develop within days. The enzyme pattern can be either hepatocellular or cholestatic. Enzyme changes may precede clinical symptoms, especially in the hepatocellular form. If a random blood test indicates mildly elevated liver enzymes, enzyme levels can be followed for a few days. Because of the rapid rise in liver enzyme levels in acute hepatitis, that condition will become evident quickly and will be easily distinguished from mild, persistent enzyme level elevations.

Acute hepatitis is a dangerous and potentially fatal condition. If it develops, the antidepressant must be discontinued and should not be introduced again, because the next reaction may be more severe.

Other Side Effects

Increased sweating can occur with the tricyclic compounds; occasionally, sweating can be marked. Carbohydrate craving also can occur, and when coupled with antihistaminic effects can lead to significant weight gain. Weight gain appears to be greater with the tertiary compounds than with the secondary agents. Sexual dysfunction has been described with the tricyclics but appears to be less common than with the SSRIs. This side effect appears to be associated with the more serotonergic compounds such as clomipramine. Tricyclic antidepressants can cause allergic skin rashes, which are sometimes associated with photosensitivity reactions. Various blood dyscrasias also have been reported; fortunately, these are very rare.

Overdose

Because antidepressants are used by depressed patients who are at risk for overdose, the lethality of antidepressant drugs in overdose is of great concern. A tricyclic overdose of 10 times the total daily dosage can be fatal (Gram 1990; Rudorfer and Robins 1982). Death most commonly results from cardiac arrhythmia. However, seizures, CNS depression, and respiratory depression also can occur. Although the use of tricyclics in depression has declined, amitriptyline remains widely used for other indications, such as pain. The total number of amitriptyline-associated deaths reported to U.S. poison control centers is more than twice the number of deaths associated with all other tricyclics and tetracyclics combined (Mowry et al. 2014). All of the tricyclic and tetracyclic compounds can be dangerous in overdose; however, two reports found that the ratio of deaths to number of prescriptions written was relatively low for clomipramine compared with that for other tricyclics (Cassidy and Henry 1987; Farmer and Pinder 1989).

Teratogenicity

The long history of tricyclic use without observation of birth defects argues for the safety of these agents. Of course, the patient must be informed of the possible risks and benefits of taking the drug and the risks of discontinuing treatment before making a decision. The risk of recurrence is particularly high during or following pregnancy for patients with a prior history of depression.

If tricyclics are continued during pregnancy, dosage adjustment may be required because of metabolic changes (Altshuler and Hendrick 1996). Drug withdrawal following delivery can occur in the infant and is characterized by tachypnea, cyanosis, irritability, and poor sucking reflex. Drugs in this class should be discontinued 1 week prior to delivery if possible. The tricyclics are excreted in breast milk at concentrations similar to those in plasma, but the actual quantity delivered is very small, so that drug levels in the infant are usually undetectable (Rudorfer and Potter 1997; also see Chapter 57, “Psychopharmacology During Pregnancy and Lactation”).

Drug–Drug Interactions

Both pharmacodynamic and pharmacokinetic drug interactions should be considered.

Pharmacodynamic Interactions

Serious pharmacodynamic interactions can occur between the tricyclics and the MAOIs. The most dangerous scenario—administration of a large dose of a tricyclic to a patient who is already taking an MAOI—could result in a sudden increase in catecholamines and a potentially fatal hypertensive reaction. Tricyclics and MAOIs have been used together to treat patients with refractory depression (Goldberg and Thornton 1978; Schuckit et al. 1971). When used in combination, treatment is begun with lower dosages, and either the two compounds are started together or the tricyclic is started first.

The most common pharmacodynamic interaction involving tricyclics occurs when they are added to other sedating agents, resulting in increased sedation. By blocking the norepinephrine transporters, the tricyclics block the uptake and thus interfere with the actions of guanethidine and tyramine. Desipramine and the other tricyclics reduce the effect of clonidine.

Quinidine is an example of a drug with a potential for dynamic and kinetic interaction with tricyclics. Because the tricyclics have quinidine-like effects, the effects of tricyclics and quinidine on cardiac conduction are potentially additive. In addition, quinidine is a potent CYP2D6 isoenzyme inhibitor that can raise tricyclic levels, further adding to the problem.

Pharmacokinetic Interactions

A number of drugs can block the metabolic pathways of the tricyclics, resulting in higher and potentially toxic blood levels of drug. Desipramine has been of particular interest because it is metabolized via the CYP2D6 isoenzyme and there are no major alternative pathways. Inhibition of CYP2D6 can result in very high desipramine plasma levels, and toxicity can occur (Preskorn et al. 1990). Quinidine, mentioned above, is a very potent CYP2D6 inhibitor. Fluoxetine and paroxetine, duloxetine, bupropion, and some antipsychotics also inhibit CYP2D6. Fluoxetine and paroxetine at usual dosages raise desipramine levels, on average, three- to fourfold in individuals who are extensive metabolizers (Preskorn et al. 1994). CYP2D6 inhibitors would be expected to block nortriptyline metabolism, but the magnitude of this interaction has not been well studied.

Because the tertiary tricyclics are metabolized by several pathways (CYP1A2, 3A4, 2C19), a selective inhibitor of one pathway would be unlikely to have a significant effect on their plasma levels. Although numerous drug interactions have been described, many are of doubtful clinical significance (for comprehensive reviews, see Nemeroff et al. 1996; Pollock 1997).

Enzyme induction can also occur, which may render the tricyclic acted upon ineffective. Unlike enzyme inhibition, which occurs quickly, enzyme induction requires synthesis of new enzyme, and the full effect may take 2–3 weeks to develop. Barbiturates and carbamazepine are potent inducers of CYP3A4; induction by phenytoin appears to be less pronounced. Although CYP2D6 is a noninducible isoenzyme, phenobarbital reduces the availability of desipramine substantially. Apparently when CYP3A4 is induced, it becomes an important metabolic pathway for desipramine and the other tricyclics. In this author’s experience, it can be difficult to attain an effective blood level of desipramine in the presence of a barbiturate.

Nicotine induces the CYP1A2 pathway and may lower concentrations of the tertiary tricyclics, but the secondary tricyclics (e.g., desipramine, nortriptyline) are less affected.

Acute ingestion of alcohol can reduce first-pass metabolism, resulting in higher tricyclic levels. Because tricyclic overdose is often associated with alcohol ingestion, this is an important consideration. Alternatively, chronic use of alcohol appears to induce hepatic isoenzymes and may lower tricyclic levels (Shoaf and Linnoila 1991).

The tricyclics themselves appear to be weak enzyme inhibitors, and few clinically significant interactions have been described. The tertiary tricyclics compete with warfarin for some metabolic enzymes (e.g., CYP1A2) and may raise warfarin levels.

Conclusion

The tricyclic drugs were the mainstay of treatment for depression for three decades. Although the second-generation antidepressants appear to be better tolerated, no new agent has been shown to be more effective than the tricyclics, and if anything, there has been concern that the new agents may be less effective. The tricyclics were “dirty” drugs; that is, they had multiple actions. Although their side effects have been emphasized, these multiple actions may contribute to their efficacy. Not only does amitriptyline block uptake of 5-HT, but its metabolite blocks uptake of norepinephrine, and in addition, amitriptyline is a 5-HT₂ antagonist. Furthermore, the anticholinergic effects of amitriptyline may contribute to antidepressant activity. The principal drawback of this class of agents is the risk of serious cardiac adverse effects. Tricyclics can aggravate arrhythmia in patients with preexisting conduction delay. They also may increase the risk of sudden death in children and in patients with ischemic heart disease. Moreover, a week’s supply of medication taken in overdose can be fatal. Because of these adverse effects, it is unlikely that there will be a resurgence of interest in the tricyclics. Nevertheless, the efficacy of these agents across a range of disorders, including pain, illustrates the potential advantages of antidepressant drugs that have multiple actions.

References

Abernethy DR, Greenblatt DJ, Shader RI: Imipramine and desipramine disposition in the elderly. J Pharmacol Exp Ther 232(1):183–188, 1985 3965690

Agency for Health Care Policy and Research: Clinical Practice Guideline: Depression in Primary Care: Treatment of Major Depression, Vol 2. Rockville, MD, U.S. Government Printing Office, 1993

Akamine Y, Yasui-Furukori N, Ieiri I, Uno T: Psychotropic drug-drug interactions involving P-glycoprotein. CNS Drugs 26(11):959–973, 2012 23023659

Altshuler LL, Hendrick VC: Pregnancy and psychotropic medication: changes in blood levels. J Clin Psychopharmacol 16(1):78–80, 1996 8834425

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition. Washington, DC, American Psychiatric Association, 1980

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). Arlington, VA, American Psychiatric Association, 2013

American Psychiatric Association Task Force on the Use of Laboratory Tests in Psychiatry: Tricyclic antidepressants—blood level measurements and clinical outcome: an APA Task Force report. Am J Psychiatry 142(2):155–162, 1985 3881999

Anderson IM: SSRIS versus tricyclic antidepressants in depressed inpatients: a meta-analysis of efficacy and tolerability. Depress Anxiety 7 (suppl 1):11–17, 1998 9597346

Anderson IM: Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability. J Affect Disord 58(1):19–36, 2000 10760555

Anderson I, Tomenson B: A meta-analysis of the efficacy of selective serotonin reuptake inhibitors compared to tricyclic antidepressants in depression (abstract). Neuropsychopharmacology 10 (suppl):106, 1994

Anton RF Jr, Burch EA Jr: Amoxapine versus amitriptyline combined with perphenazine in the treatment of psychotic depression. Am J Psychiatry 147(9):1203–1208, 1990 2201223

Axelrod J, Whitby LG, Hertting G: Effect of psychotropic drugs on the uptake of H3-norepinephrine by tissues. Science 133(3450):383–384, 1961 13685337

Barden N: Modulation of glucocorticoid receptor gene expression by antidepressant drugs. Pharmacopsychiatry 29(1):12–22, 1996 8852529

Bertilsson L, Mellström B, Sjöqvist F: Pronounced inhibition of noradrenaline uptake by 10-hydroxymetabolites of nortriptyline. Life Sci 25(15):1285–1292, 1979 513959

Biederman J, Baldessarini RJ, Wright V, et al: A double-blind placebo controlled study of desipramine in the treatment of ADD, I: efficacy. J Am Acad Child Adolesc Psychiatry 28(5):777–784, 1989 2676967

Biederman J, Baldessarini RJ, Goldblatt A, et al: A naturalistic study of 24-hour electrocardiographic recordings and echocardiographic findings in children and adolescents treated with desipramine. J Am Acad Child Adolesc Psychiatry 32(4):805–813, 1993 8340302

Blier P, de Montigny C, Chaput Y: Modifications of the serotonin system by antidepressant treatments: implications for the therapeutic response in major depression. J Clin Psychopharmacol 7 (6 suppl):24S–35S, 1987 3323264

Bock JL, Nelson JC, Gray S, Jatlow PI: Desipramine hydroxylation: variability and effect of antipsychotic drugs. Clin Pharmacol Ther 33(3):322–328, 1983 6130865

Bolden-Watson C, Richelson E: Blockade by newly-developed antidepressants of biogenic amine uptake into rat brain synaptosomes. Life Sci 52(12):1023–1029, 1993 8445992

Breitenstein B, Brückl TM, Ising M, et al: ABCB1 gene variants and antidepressant treatment outcome: a meta-analysis. Am J Med Genet B Neuropsychiatr Genet 168B(4):274–283, 2015 25847751

Brøsen K, Otton SV, Gram LF: Sparteine oxidation polymorphism in Denmark. Acta Pharmacol Toxicol (Copenh) 57(5):357–360, 1985 4090995

Brøsen K, Zeugin T, Meyer UA: Role of P450 IID6, the target of the sparteine-debrisoquin oxidation polymorphism, in the metabolism of imipramine. Clin Pharmacol Ther 49(6):609–617, 1991 2060250

Bunney WE Jr, Davis JM: Norepinephrine in depressive reactions. A review. Arch Gen Psychiatry 13(6):483–494, 1965 5320621

Bymaster FP, Katner JS, Nelson DL, et al: Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology 27(5):699–711, 2002 12431845

Cassidy S, Henry J: Fatal toxicity of antidepressant drugs in overdose. Br Med J (Clin Res Ed) 295(6605):1021–1024, 1987 3690249

Chan CH, Janicak PG, Davis JM, et al: Response of psychotic and nonpsychotic depressed patients to tricyclic antidepressants. J Clin Psychiatry 48(5):197–200, 1987 3571174

Charney DS, Delgado PL, Price LH, et al: The receptor sensitivity hypothesis of antidepressant action: a review of antidepressant effects on serotonin function, in The Role of Serotonin in Psychiatric Disorders. Edited by Brown SL, van Praag HM. New York, Brunner/Mazel, 1991, pp 29–56

Coupet J, Rauh CE, Szues-Myers VA, Yunger LM: 2-Chloro-11-(1-piperazinyl)dibenz[b, f] [1, 4]oxazepine (amoxapine), an antidepressant with antipsychotic properties—a possible role for 7-hydroxyamoxapine. Biochem Pharmacol 28(16):2514–2515, 1979 41531

Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl) 114(4):559–565, 1994 7855217

Davis JM, Glassman AH: Antidepressant drugs, in Comprehensive Textbook of Psychiatry. Edited by Kaplan HI, Sadock BJ. Baltimore, MD, Williams & Wilkins, 1989, pp 1627–1655

Delgado PL, Charney DS, Price LH, et al: Serotonin function and the mechanism of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Arch Gen Psychiatry 47(5):411–418, 1990 2184795

Delgado PL, Miller HL, Salomon RM, et al: Monoamines and the mechanism of antidepressant action: effects of catecholamine depletion on mood of patients treated with antidepressants. Psychopharmacol Bull 29(3):389–396, 1993 8121966

de Montigny C, Aghajanian GK: Tricyclic antidepressants: long-term treatment increases responsivity of rat forebrain neurons to serotonin. Science 202(4374):1303–1306, 1978 725608

DiMascio A, Heninger G, Klerman GL: Psychopharmacology of imipramine and desipramine: a comparative study of their effects in normal males. Psychopharmacology (Berl) 5:361–371, 1964 14151549

Duman RS, Heninger GR, Nestler EJ: A molecular and cellular theory of depression. Arch Gen Psychiatry 54(7):597–606, 1997 9236543

Eberhard G, von Knorring L, Nilsson HL, et al: A double-blind randomized study of clomipramine versus maprotiline in patients with idiopathic pain syndromes. Neuropsychobiology 19(1):25–34, 1988 3054623

Evans DAP, Mahgoub A, Sloan TP, et al: A family and population study of the genetic polymorphism of debrisoquine oxidation in a white British population. J Med Genet 17(2):102–105, 1980 7381862

Farmer RD, Pinder RM: Why do fatal overdose rates vary between antidepressants? Acta Psychiatr Scand Suppl 354:25–35, 1989 2589101

Frank E, Kupfer DJ, Perel JM, et al: Three-year outcomes for maintenance therapies in recurrent depression. Arch Gen Psychiatry 47(12):1093–1099, 1990 2244793

Furey ML, Drevets WC: Antidepressant efficacy of the antimuscarinic drug scopolamine: a randomized, placebo-controlled clinical trial. Arch Gen Psychiatry 63(10): 1121–1129, 2006 17015814

Geller B: Psychopharmacology of children and adolescents: pharmacokinetics and relationships of plasma/serum levels to response. Psychopharmacol Bull 27(4):401–409, 1991 1813890

Gerson SC, Plotkin DA, Jarvik LF: Antidepressant drug studies, 1964 to 1986: empirical evidence for aging patients. J Clin Psychopharmacol 8(5):311–322, 1988 3053796

Glassman AH, Bigger JT Jr: Cardiovascular effects of therapeutic doses of tricyclic antidepressants. A review. Arch Gen Psychiatry 38(7):815–820, 1981 7247643

Glassman AH, Kantor SJ, Shostak M: Depression, delusions, and drug response. Am J Psychiatry 132(7):716–719, 1975 1094841

Glassman AH, Perel JM, Shostak M, et al: Clinical implications of imipramine plasma levels for depressive illness. Arch Gen Psychiatry 34(2):197–204, 1977 843179

Glassman AH, Bigger JT Jr, Giardina EV, et al: Clinical characteristics of imipramine-induced orthostatic hypotension. Lancet 1(8114):468–472, 1979 85056

Glassman AH, Roose SP, Bigger JT Jr: The safety of tricyclic antidepressants in cardiac patients. Risk-benefit reconsidered. JAMA 269(20):2673–2675, 1993 8487453

Goldberg RS, Thornton WE: Combined tricyclic-MAOI therapy for refractory depression: a review, with guidelines for appropriate usage. J Clin Pharmacol 18(2-3):143–147, 1978 342553

Goodwin FK, Bunney WE Jr: Depressions following reserpine: a reevaluation. Semin Psychiatry 3(4):435–448, 1971 4154501

Goodwin GM, Green AR, Johnson P: 5-HT2 receptor characteristics in frontal cortex and 5-HT2 receptor-mediated head-twitch behaviour following antidepressant treatment to mice. Br J Pharmacol 83(1):235–242, 1984 6237705

Gram LF: Inadequate dosing and pharmacokinetic variability as confounding factors in assessment of efficacy of antidepressants. Clin Neuropharmacol 13 (suppl 1): S35–S44, 1990 2199035

Greenblatt DJ, Moltke LL, Shader RI: Pharmacokinetics of psychotropic drugs, in Geriatric Psychopharmacology. Edited by Nelson JC. New York, Marcel Dekker, 1998, pp 27–41

Greist JH, Jefferson JW, Kobak KA, et al: Efficacy and tolerability of serotonin transport inhibitors in obsessive-compulsive disorder. A meta-analysis. Arch Gen Psychiatry 52(1):53–60, 1995 7811162

Hammer W, Sjöqvist F: Plasma levels of monomethylated tricyclic antidepressants during treatment with imipramine-like compounds. Life Sci 6(17):1895–1903, 1967 6052684

Himmelhoch JM, Detre T, Kupfer DJ, et al: Treatment of previously intractable depressions with tranylcypromine and lithium. J Nerv Ment Dis 155(3):216–220, 1972 5053920

Himmelhoch JM, Thase ME, Mallinger AG, Houck P: Tranylcypromine versus imipramine in anergic bipolar depression. Am J Psychiatry 148(7):910–916, 1991 2053632

Horst DA, Grace ND, LeCompte PM: Prolonged cholestasis and progressive hepatic fibrosis following imipramine therapy. Gastroenterology 79(3):550–554, 1980 7429116

Ji L, Pan S, Marti-Jaun J, et al: Single-step assays to analyze CYP2D6 gene polymorphisms in Asians: allele frequencies and a novel *14B allele in mainland Chinese. Clin Chem 48(7):983–988, 2002 12089164

Jick H, Dinan BJ, Hunter JR, et al: Tricyclic antidepressants and convulsions. J Clin Psychopharmacol 3(3):182–185, 1983 6875026

Jobson K, Linnoila M, Gillam J, Sullivan JL: Successful treatment of severe anxiety attacks with tricyclic antidepressants: a potential mechanism of action. Am J Psychiatry 135(7):863–864, 1978 665806

Johannessen Landmark C, Henning O, Johannessen SI: Proconvulsant effects of antidepressants—What is the current evidence? Epilepsy Behav 61:287–291, 2016 26926001

Katz IR, Simpson GM, Jethanandani V, et al: Steady state pharmacokinetics of nortriptyline in the frail elderly. Neuropsychopharmacology 2(3):229–236, 1989 2789662

Katz IR, Simpson GM, Curlik SM, et al: Pharmacologic treatment of major depression for elderly patients in residential care settings. J Clin Psychiatry 51 (7 suppl):41–47, discussion 48, 1990 2195013

Keller MB, Gelenberg AJ, Hirschfeld RMA, et al: The treatment of chronic depression, part 2: a double-blind, randomized trial of sertraline and imipramine. J Clin Psychiatry 59(11):598–607, 1998 9862606

Klein DF: Delineation of two drug responsive anxiety syndromes. Psychopharmacology (Berl) 5:397–408, 1964 14194683

Kocsis JH, Frances AJ, Voss C, et al: Imipramine treatment for chronic depression. Arch Gen Psychiatry 45(3):253–257, 1988 3277579

Kuhn R: The treatment of depressive states with G 22355 (imipramine hydrochloride). Am J Psychiatry 115(5):459–464, 1958 13583250

Kuhn R: The imipramine story, in Discoveries in Biological Psychiatry. Edited by Ayd FJ, Blackwell B. Philadelphia, PA, JB Lippincott, 1970, pp 205–217

Kupfer DJ, Spiker DG: Refractory depression: prediction of non-response by clinical indicators. J Clin Psychiatry 42(8):307–312, 1981 7251567

Lakoski JM, Aghajanian GK: Effects of ketanserin on neuronal responses to serotonin in the prefrontal cortex, lateral geniculate and dorsal raphe nucleus. Neuropharmacology 24(4):265–273, 1985 3158835

Leonard HL, Swedo S, Rapoport JL, et al: Treatment of obsessive compulsive disorder in children and adolescents with clomipramine and desipramine: a double-blind crossover comparison. Arch Gen Psychiatry 46:1088–1092, 1989 2686576

Lesch KP, Manji HK: Signal-transducing G proteins and antidepressant drugs: evidence for modulation of alpha subunit gene expression in rat brain. Biol Psychiatry 32(7):549–579, 1992 1333286

Liang J, Liu X, Pan M, et al: Blockade of Nav1.8 currents in nociceptive trigeminal neurons contributes to anti-trigeminovascular nociceptive effect of amitriptyline. Neuromolecular Med 16(2):308–321, 2014 24292897

Liebowitz MR, Quitkin FM, Stewart JW, et al: Phenelzine vs imipramine in atypical depression. Arch Gen Psychiatry 41:669–677, 1984 6375621

Liebowitz MR, Quitkin FM, Stewart JW, et al: Antidepressant specificity in atypical depression. Arch Gen Psychiatry 45(2):129–137, 1988 3276282

Livingston RL, Zucker DK, Isenberg K, Wetzel RD: Tricyclic antidepressants and delirium. J Clin Psychiatry 44(5):173–176, 1983 6853452

Manji HK, Potter WZ, Lenox RH: Signal transduction pathways. Molecular targets for lithium’s actions. Arch Gen Psychiatry 52(7):531–543, 1995 7598629

Marek GJ, Carpenter LL, McDougle CJ, Price LH: Synergistic action of 5-HT2A antagonists and selective serotonin reuptake inhibitors in neuropsychiatric disorders. Neuropsychopharmacology 28(2):402–412, 2003 12589395

Max MB, Lynch SA, Muir J, et al: Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med 326(19):1250–1256, 1992 1560801

McGrath PJ, Stewart JW, Harrison W, Quitkin FM: Treatment of tricyclic refractory depression with a monoamine oxidase inhibitor antidepressant. Psychopharmacol Bull 23(1):169–172, 1987 3602314

Miller NL, Kocsis JH, Leon AC, et al: Maintenance desipramine for dysthymia: a placebo-controlled study. J Affect Disord 64(2-3):231–237, 2001 11313089

Mochizucki D: Serotonin and noradrenaline reuptake inhibitors in animal models of pain. Hum Psychopharmacol 19 (suppl 1):S15–S19, 2004 15378668

Montgomery SA: The efficacy of fluoxetine as an antidepressant in the short and long term. Int Clin Psychopharmacol 4 (suppl 1):113–119, 1989 2644336

Moskovitz R, DeVane CL, Harris R, Stewart RB: Toxic hepatitis and single daily dosage imipramine therapy. J Clin Psychiatry 43(4):165–166, 1982 7068550

Mowry JB, Spyker DA, Cantilena LR Jr, et al: 2013 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 31st Annual Report. Clin Toxicol (Phila) 52(10):1032–1283, 2014 25559822

Munjack DJ, Usigli R, Zulueta A, et al: Nortriptyline in the treatment of panic disorder and agoraphobia with panic attacks. J Clin Psychopharmacol 8(3):204–207, 1988 3379145

Nelson JC: Use of desipramine in depressed inpatients. J Clin Psychiatry 45(10 Pt 2): 10–16, 1984 6384205

Nelson JC: The use of antipsychotic drugs in the treatment of depression, in Treating Resistant Depression. Edited by Zohar J, Belmaker RH. New York, PMA Publishing, 1987, pp 131–146

Nelson JC, Jatlow PI: Nonlinear desipramine kinetics: prevalence and importance. Clin Pharmacol Ther 41(6):666–670, 1987 3581650

Nelson JC, Jatlow P, Quinlan DM, Bowers MB Jr: Desipramine plasma concentration and antidepressant response. Arch Gen Psychiatry 39(12):1419–1422, 1982 7149903

Nelson JC, Jatlow PI, Quinlan DM: Subjective complaints during desipramine treatment. Relative importance of plasma drug concentrations and the severity of depression. Arch Gen Psychiatry 41(1): 55–59, 1984 6691785

Nelson JC, Jatlow PI, Mazure C: Desipramine plasma levels and response in elderly melancholic patients. J Clin Psychopharmacol 5(4):217–220, 1985 4019810

Nelson JC, Jatlow PI, Mazure C: Rapid desipramine dose adjustment using 24-hour levels. J Clin Psychopharmacol 7(2):72–77, 1987 3584524

Nelson JC, Atillasoy E, Mazure C, Jatlow PI: Hydroxydesipramine in the elderly. J Clin Psychopharmacol 8(6):428–433, 1988a 3235701

Nelson JC, Mazure C, Jatlow PI: Antidepressant activity of 2-hydroxydesipramine. Clin Pharmacol Ther 44(3):283–288, 1988b 3416551

Nelson JC, Mazure CM, Jatlow PI: Characteristics of desipramine-refractory depression. J Clin Psychiatry 55(1):12–19, 1994 8294386

Nelson JC, Mazure CM, Jatlow PI: Desipramine treatment of major depression in patients over 75 years of age. J Clin Psychopharmacol 15(2):99–105, 1995 7782495

Nemeroff CB, DeVane CL, Pollock BG: Newer antidepressants and the cytochrome P450 system. Am J Psychiatry 153(3):311–320, 1996 8610817

Nibuya M, Nestler EJ, Duman RS: Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci 16(7):2365–2372, 1996 8601816

Nordin C, Bertilsson L, Siwers B: Clinical and biochemical effects during treatment of depression with nortriptyline: the role of 10-hydroxynortriptyline. Clin Pharmacol Ther 42(1):10–19, 1987 2439250

O’Brien FE, Dinan TG, Griffin BT, Cryan JF: Interactions between antidepressants and P-glycoprotein at the blood-brain barrier: clinical significance of in vitro and in vivo findings. Br J Pharmacol 165(2):289–312, 2012 21718296

O’Malley PG, Jackson JL, Santoro J, et al: Antidepressant therapy for unexplained symptoms and symptom syndromes. J Fam Pract 48(12):980–990, 1999 10628579

Panerai AE, Monza G, Movilia P, et al: A randomized, within-patient, cross-over, placebo-controlled trial on the efficacy and tolerability of the tricyclic antidepressants chlorimipramine and nortriptyline in central pain. Acta Neurol Scand 82(1):34–38, 1990 2239134

Peck AW, Stern WC, Watkinson C: Incidence of seizures during treatment with tricyclic antidepressant drugs and bupropion. J Clin Psychiatry 44(5 Pt 2):197–201, 1983 6406457

Peroutka SJ, Snyder SH: Long-term antidepressant treatment decreases spiroperidol-labeled serotonin receptor binding. Science 210(4465):88–90, 1980 6251550

Pollock BG: Drug interactions, in Geriatric Psychopharmacology. Edited by Nelson JC. New York, Marcel Dekker, 1997, pp 43–60

Potter WZ, Calil HM, Manian AA, et al: Hydroxylated metabolites of tricyclic antidepressants: preclinical assessment of activity. Biol Psychiatry 14(4):601–613, 1979 486616

Powell WJ Jr, Koch-Weser J, Williams RA: Lethal hepatic necrosis after therapy with imipramine and desipramine. JAMA 206(3):642–645, 1968 4234079

Prange AJ Jr: The pharmacology and biochemistry of depression. Dis Nerv Syst 25:217–221, 1964 14140032

Preskorn SH, Irwin HA: Toxicity of tricyclic antidepressants—kinetics, mechanism, intervention: a review. J Clin Psychiatry 43(4):151–156, 1982 7068546

Preskorn SH, Simpson S: Tricyclic-antidepressant-induced delirium and plasma drug concentration. Am J Psychiatry 139(6):822–823, 1982 7081500

Preskorn SH, Beber JH, Faul JC, Hirschfeld RM: Serious adverse effects of combining fluoxetine and tricyclic antidepressants. Am J Psychiatry 147(4):532, 1990 2107764

Preskorn SH, Alderman J, Chung M, et al: Pharmacokinetics of desipramine coadministered with sertraline or fluoxetine. J Clin Psychopharmacol 14(2):90–98, 1994 8195463

Price LH, Nelson JC, Waltrip RW: Desipramine-associated hepatitis. J Clin Psychopharmacol 3(4):243–246, 1983 6886037

Price LH, Nelson JC, Jatlow PI: Effects of desipramine on clinical liver function tests. Am J Psychiatry 141(6):798–800, 1984 6731623

Priest BT, Kaczorowski GJ: Blocking sodium channels to treat neuropathic pain. Expert Opin Ther Targets 11(3):291–306, 2007 17298289

Randrup A, Braestrup C: Uptake inhibition of biogenic amines by newer antidepressant drugs: relevance to the dopamine hypothesis of depression. Psychopharmacology (Berl) 53(3):309–314, 1977 408861

Rapoport J, Potter WZ: Tricyclic antidepressants: use in pediatric psychopharmacology, in Pharmacokinetics: Youth and Age. Edited by Raskin A, Robinson D. Amsterdam, The Netherlands, Elsevier, 1981, pp 105–123

Rapoport JL, Mikkelsen EJ, Zavadil A, et al: Childhood enuresis. II. Psychopathology, tricyclic concentration in plasma, and antienuretic effect. Arch Gen Psychiatry 37(10):1146–1152, 1980 7000030

Reynolds CF 3rd, Butters MA, Lopez O, et al: Maintenance treatment of depression in old age: a randomized, double-blind, placebo-controlled evaluation of the efficacy and safety of donepezil combined with antidepressant pharmacotherapy. Arch Gen Psychiatry 68(1):51–60, 2011 21199965

Richelson E, Nelson A: Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro. J Pharmacol Exp Ther 230(1):94–102, 1984 6086881

Riddle MA, Nelson JC, Kleinman CS, et al: Sudden death in children receiving Norpramin: a review of three reported cases and commentary. J Am Acad Child Adolesc Psychiatry 30(1):104–108, 1991 2005044

Riddle MA, Geller B, Ryan N: Another sudden death in a child treated with desipramine. J Am Acad Child Adolesc Psychiatry 32(4):792–797, 1993 8340300

Roose SP, Glassman AH, Siris SG, et al: Comparison of imipramine- and nortriptyline-induced orthostatic hypotension: a meaningful difference. J Clin Psychopharmacol 1(5):316–319, 1981 6277997

Roose SP, Glassman AH, Walsh BT, Woodring S: Tricyclic nonresponders: phenomenology and treatment. Am J Psychiatry 143(3):345–348, 1986 3953869

Roose SP, Glassman AH, Giardina EG, et al: Cardiovascular effects of imipramine and bupropion in depressed patients with congestive heart failure. J Clin Psychopharmacol 7(4):247–251, 1987a 3114333

Roose SP, Glassman AH, Giardina EG, et al: Tricyclic antidepressants in depressed patients with cardiac conduction disease. Arch Gen Psychiatry 44(3):273–275, 1987b 3827520

Roose SP, Laghrissi-Thode F, Kennedy JS, et al: Comparison of paroxetine and nortriptyline in depressed patients with ischemic heart disease. JAMA 279(4):287–291, 1998 9450712

Rosenstein DL, Nelson JC: Heart rate during desipramine treatment as an indicator of beta₁-adrenergic function. Society of Biological Psychiatry Scientific Program. Biol Psychiatry 29:132A, 1991

Rosenstein DL, Nelson JC, Jacobs SC: Seizures associated with antidepressants: a review. J Clin Psychiatry 54(8):289–299, 1993 8253696

Rudorfer MV, Potter WZ: The role of metabolites of antidepressant in the treatment of depression. CNS Drugs 7:273–312, 1997

Rudorfer MV, Robins E: Amitriptyline overdose: clinical effects on tricyclic antidepressant plasma levels. J Clin Psychiatry 43(11):457–460, 1982 7174623

Rudorfer MV, Young RC: Desipramine: cardiovascular effects and plasma levels. Am J Psychiatry 137(8):984–986, 1980 7416309

Ryan ND: The pharmacologic treatment of child and adolescent depression. Psychiatr Clin North Am 15(1):29–40, 1992 1549547

Salerno SM, Browning R, Jackson JL: The effect of antidepressant treatment on chronic back pain: a meta-analysis. Arch Intern Med 162(1):19–24, 2002 11784215

Schildkraut JJ: The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry 122(5): 509–522, 1965 5319766

Schuckit M, Robins E, Feighner J: Tricyclic antidepressants and monoamine oxidase inhibitors. Arch Gen Psychiatry 24(6):509–514, 1971 5578096

Schwaninger M, Schöfl C, Blume R, et al: Inhibition by antidepressant drugs of cyclic AMP response element-binding protein/cyclic AMP response element-directed gene transcription. Mol Pharmacol 47(6):1112–1118, 1995 7603449

Shoaf SE, Linnoila M: Interaction of ethanol and smoking on the pharmacokinetics and pharmacodynamics of psychotropic medications. Psychopharmacol Bull 27(4):577–594, 1991 1813903

Siris SG, van Kammen DP, Docherty JP: Use of antidepressant drugs in schizophrenia. Arch Gen Psychiatry 35(11):1368–1377, 1978 30429

Spiker DG, Weiss AN, Chang SS, et al: Tricyclic antidepressant overdose: clinical presentation and plasma levels. Clin Pharmacol Ther 18(5 Pt 1):539–546, 1975 1183139

Spiker DG, Weiss JC, Dealy RS, et al: The pharmacological treatment of delusional depression. Am J Psychiatry 142(4):430–436, 1985 3883815

Sulser F, Vetulani J, Mobley PL: Mode of action of antidepressant drugs. Biochem Pharmacol 27(3):257–261, 1978 202286

Szabo ST, Blier P: Effect of the selective noradrenergic reuptake inhibitor reboxetine on the firing activity of noradrenaline and serotonin neurons. Eur J Neurosci 13(11):2077–2087, 2001 11422448

Tatsumi M, Groshan K, Blakely RD, Richelson E: Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol 340(2–3):249–258, 1997 9537821

Thase ME, Mallinger AG, McKnight D, Himmelhoch JM: Treatment of imipramine-resistant recurrent depression, IV: A double-blind crossover study of tranylcypromine for anergic bipolar depression. Am J Psychiatry 149(2):195–198, 1992 1734739

Thase ME, Fava M, Halbreich U, et al: A placebo-controlled, randomized clinical trial comparing sertraline and imipramine for the treatment of dysthymia. Arch Gen Psychiatry 53(9):777–784, 1996 8792754

Thayssen P, Bjerre M, Kragh-Sørensen P, et al: Cardiovascular effect of imipramine and nortriptyline in elderly patients. Psychopharmacology (Berl) 74(4):360–364, 1981 6794083

Tremblay P, Blier P: Catecholaminergic strategies for the treatment of major depression. Curr Drug Targets 7(2):149–158, 2006 16475956

Uhr M, Tontsch A, Namendorf C, et al: Polymorphisms in the drug transporter gene ABCB1 predict antidepressant treatment response in depression. Neuron 57(2): 203–209, 2008 18215618

von Moltke LL, Greenblatt DJ, Harmatz JS, et al: Psychotropic drug metabolism in old age: principles and problems of assessment, in Psychopharmacology: The Fourth Generation of Progress. Edited by Bloom FE, Kupfer DJ. New York, Raven, 1995, pp 1461–1469

Walsh BT, Hadigan CM, Wong LM: Increased pulse and blood pressure associated with desipramine treatment of bulimia nervosa. J Clin Psychopharmacol 12(3):163–168, 1992 1629381

Weaver GA, Pavlinac D, Davis JS: Hepatic sensitivity to imipramine. Am J Dig Dis 22(6):551–553, 1977 868834

Weiss J, Dormann SM, Martin-Facklam M, et al: Inhibition of P-glycoprotein by newer antidepressants. J Pharmacol Exp Ther 305(1):197–204, 2003 12649369

Wehr TA, Goodwin FK: Can antidepressants cause mania and worsen the course of affective illness? Am J Psychiatry 144(11): 1403–1411, 1987 3314536

Wilens TE, Biederman J, Baldessarini RJ, et al: Developmental changes in serum concentrations of desipramine and 2-hydroxydesipramine during treatment with desipramine. J Am Acad Child Adolesc Psychiatry 31(4):691–698, 1992 1644733

Wilens TE, Biederman J, Prince J, et al: Six-week, double-blind, placebo-controlled study of desipramine for adult attention deficit hyperactivity disorder. Am J Psychiatry 153(9):1147–1153, 1996 8780417

Yoshimura M, Furue H: Mechanisms for the anti-nociceptive actions of the descending noradrenergic and serotonergic systems in the spinal cord. J Pharmacol Sci 101(2):107–117, 2006 16766858

Young RC, Alexopoulos GS, Shamoian CA, et al: Plasma 10-hydroxynortriptyline in elderly depressed patients. Clin Pharmacol Ther 35(4):540–544, 1984 6705454

Yue QY, Zhong ZH, Tybring G, et al: Pharmacokinetics of nortriptyline and its 10-hydroxy metabolite in Chinese subjects of different CYP2D6 genotypes. Clin Pharmacol Ther 64(4):384–390, 1998 9797795

Zitrin CM, Klein DF, Woerner MG: Treatment of agoraphobia with group exposure in vivo and imipramine. Arch Gen Psychiatry 37(1):63–72, 1980 6101535