What is the function of tricyclic antidepressants?

Tricyclic antidepressants.

TCAs used for chronic pain management include amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, nortriptyline, and protriptyline. Among these drugs, amitriptyline and nortriptyline have the largest body of reassuring safety data in pregnancy and lactation. TCAs cross the placenta; the approximate F/M ratio is 0.6.116

Although most epidemiologic studies show no association between maternal TCA use and the risk for major congenital malformation, the largest and most recent studies have yielded conflicting results.69,117,118 Using data from a research database from five U.S. health maintenance organizations, investigators identified 221 infants exposed to TCAs and compared them to almost 50,000 infants without exposure.117 No increased risk for major congenital malformations was identified (RR, 0.86; 95% CI, 0.57 to 1.3). Similarly, in a large 2013 study of 1608 women exposed to TCAs, 1875 women exposed to selective serotonin reuptake inhibitors (SSRIs), and 6617 women with no exposure to any antidepressants during pregnancy, no increased risk for congenital anomalies with TCA exposure was observed (RR, 0.9; 95% CI, 0.6 to 1.2).69 By contrast, a large Swedish registry study published in 2010 identified a possible link betweenin utero exposure to TCAs and an increased risk for congenital malformations.118 Almost 2500 women who took TCAs during pregnancy (early pregnancy,n = 1662; later pregnancy,n = 782) were compared with over 1 million control patients in the same population. A small increase in the risk for severe malformations (aOR, 1.36; 95% CI, 1.07 to 1.72) as well as overall cardiac malformations (aOR, 1.63; 95% CI, 1.12 to 2.36) was identified after adjusting for maternal age, parity, smoking, and body mass index (but not psychiatric diagnoses or concurrent medication use).118 Among the TCAs, clomipramine was the most strongly implicated in increased risk, although in most studies, amitriptyline is the most commonly prescribed TCA.118 Overall rates of congenital malformations in this study were less than 5%, even in the TCA group. Many smaller studies have failed to show any link between maternal TCA use and increased risk for congenital anomalies.68,87

There are some reports of neonatal symptoms possibly related to TCA withdrawal, including transient tachypnea, tachycardia, irritability, spasms, hypertonus, and clonus.68 A meta-analysis spanning studies from 1966 to 2010 found that TCAs, mostly clomipramine, were associated with transient poor neonatal adaptation, including an increased rate of respiratory distress, temperature instability, hypoglycemia, and convulsions.119 Thus, close observation of the neonate in the immediate postdelivery period is likely warranted.

Pre-Clinical Research

Tricyclic antidepressants (TCAs) are potent inhibitors of norepinephrine and/or serotonin reuptake in vitro and in vivo and are active in animal models of depression such as, learned helplessness model and reversal of reserpine-induced behavioral syndrome, among others.

Furthermore, many TCAs are known to antagonize muscarinic cholinergic receptors, histamine (H1) receptors, alpha-1 adrenoceptors, and sodium and calcium cardiac channels Pacher et al (2001). The effects on these neurotransmitter receptors are thought not to contribute to their antidepressant effects, but are responsible for their undesirable anticholinergic, antihistaminergic, and cardiotoxic side effects Pacher et al (2001).

TCA peels

TCA is usually used to achieve medium-depth peels. The recovery time can range from 5 to 10 days and the procedure can be associated with significant discomfort while the peel is performed. However, the pain usually subsides before the patient goes home. Patients receiving intramuscular or IV sedation tolerate the procedure better and allow the peel to proceed at a faster speed. Additional pain control can be achieve with the use of strong fans or cooling units with refrigerated air and oral sedation. Topical anesthetics should not be used prior to skin peels since they enhance the penetration of the TCA and may result in an undesirable depth of peel.

Skin resurfacing, whether with peels or lasers, is all about reading the skin depth signs properly. Regardless of the type of TCA peel performed, the evolving clinical depth signs remain the same. The only difference between the various peels is the speed by which these signs appear.

Physicians with minimal peeling experience are encouraged to start with relatively slower peeling techniques prior to proceeding to faster peels. Combination peels using a keratolytic peel followed by a TCA peel will speed up the penetration of the TCA, therefore carrying the risk of penetrating deeper than expected. Just like with laser resurfacing and dermabrasion, physicians must keep in mind the anatomic variations of skin thickness prior to resurfacing.

Residual oil or thick scale may lead to a patchy peel; therefore, it is essential to cleanse and degrease the face well prior to proceeding. Clinical depth signs are very important to monitor during the peeling process.26 Frost appears on the skin gradually as a result of coagulation of epidermal and dermal proteins by the action of trichloroacetic acid.20 As TCA is first applied, a light, non-organized frost begins to form (level 1 frost) (Figs. 5.5.4A & 5.5.5A).

Further application results in the frost being solid but with a diffuse pink background (vasodilation; level 2 frost) (Fig. 5.5.4B); this level of frost indicates a peel to the level of the papillary dermis. The pink background of the frost is referred to as the “pink sign”20 (Fig. 5.5.5B). The “pink sign” will be apparent as long as the blood vessels of the papillary dermis are still intact with normal blood flow. This “pink sign” is the endpoint for the standard, papillary dermis-level peel.

Additional chemical peel solution application will result in further protein coagulation, a more solid white frost, and the loss of the “pink sign” indicating coagulation of the papillary dermis vascular plexus (level 3 frost) (Fig. 5.5.4C).

The “pink sign” is difficult to see in darker skin. When peeling dark skinned individuals, the “epidermal sliding” must be used to gauge depth.20 The “epidermal sliding” sign shows up as exaggerated wrinkling of the skin that occurs prior to complete precipitation and coagulation of papillary dermis proteins (seeFig. 5.5.5B). At this point, papillary dermal edema and disruption of anchoring fibrils allows the epidermis to be more freely movable, resulting in wrinkling in an exaggerated fashion when the skin is pushed or pinched. This sign will disappear when the papillary dermis protein becomes coagulated and adherent to the epidermal coagulated proteins, thus indicating that the peel depth has reached the superficial reticular dermis (Fig. 5.5.5C). At this point, the pink background also becomes lost. In thick skin, “epidermal sliding” may not be very obvious and the “pink sign” alone has to be used to indicate the peel depth.

Extrapyramidal symptoms

Tricyclic antidepressants are often listed among the many drugs that can produce buccofaciolingual or choreoathetoid movements [75]. A putative mechanism is a central anticholinergic action, which upsets the balance between the dopaminergic and cholinergic systems. The spontaneous occurrence of this syndrome makes it difficult to establish a cause-and-effect relation, although both patients described in the above report had symptoms again when rechallenged.

There is a more clear-cut cause-and-effect relation in the parkinsonian symptoms that occasionally occur with high-dosage tricyclic therapy in susceptible individuals (particularly elderly women). Because of its piperazine side-chain and structural resemblance to the phenothiazines, amoxapine has antidopaminergic properties that appear to produce typical dystonic reactions [76], but other tricyclic antidepressants may also be implicated in producing the full range of so-called extrapyramidal syndromes, including akathisia, dystonic reactions, parkinsonism, and tardive dyskinesia. Case reports have been described before [77–79]. In the reports of tardive dyskinesia the problem is often that these patients have taken many different drugs.

Tricyclic Antidepressants

TCAs have been demonstrated to decrease the amount of time spent in REM sleep, stimulate ADH secretion, and relax the detrusor muscle via weak anticholinergic properties. Its anti-enuretic effect has been theorized to be less likely because of its action at the kidney or bladder level and more likely a result of noradrenergic stimulation at the brainstem, specifically the locus coeruleus (Gepertz and Nevéus, 2004). Given the efficacy and safety of enuresis alarms and DDAVP, TCAs (e.g., imipramine, amitriptyline, and desipramine) are considered a third-line treatment for therapy-resistant MSE (Nevéus et al., 2010).

Level 1 evidence demonstrates that, compared with placebo, TCAs are more effective at reducing the number of wet nights and at achieving 14 consecutive dry nights (i.e., cure) but essentially become ineffective once treatment is discontinued.

Further information on this topic is available online atExpertConsult.com.

In a recent systematic review, treatment with TCAs was associated with a reduction of approximately one wet night per week compared with placebo (Glazener and Evans, 2000). Approximately 20% of children became dry during therapy versus 5% with placebo. The rate of relapse was 96% after discontinuation of therapy. In an observational study of children who were refractory to first-line therapy, researchers found that approximately one-third of children became dry on monotherapy, one-third became dry after adding DDAVP, and the remaining one-third were nonresponders (Gepertz and Nevéus, 2004).

Although other TCAs are effective, imipramine is used most often in the treatment of enuresis. Imipramine is available in 10-, 25-, and 50-mg tablets. The initial dose is 10 to 25 mg 1 hour before bedtime; it may be increased by 25 mg if there is no response after 1 week (Schmitt, 1997). On average, the bedtime dose is 25 mg for children 5 to 8 years of age and 50 mg for older children. The dose should not exceed 50 mg in children between 6 and 12 years of age and 75 mg in children older than 12 years of age (Glazener and Evans, 2000).

The response to imipramine should be assessed after 1 month. If there is no improvement after 3 months, it should be discontinued as a gradual taper (as is done with other TCAs). As is the case with other pharmacotherapy for enuresis, we give patients a drug holiday every 3 to 6 months, gradually tapering the dose over a 2-week period (Gepertz and Nevéus, 2004).

Imiprimine is also an effective method of treating refractory daytime incontinence; in a pediatric population of 163 patients, 53% experienced complete treatment response as assessed by the Vancouver Symptom Score (VSS). Of the patients included in this retrospective study, only 13.3% experienced adverse effects (Franco et al., 2018).

Adverse effects of TCA therapy are relatively uncommon. Approximately 5% of children treated with TCAs develop neurologic symptoms, including nervousness, personality change, and disordered sleep. TCAs (as with other antidepressants) are required by the FDA to carry a black box warning regarding the possibility of increased suicidality, particularly in individuals with preexisting depressive symptoms.The most serious adverse effects of TCAs involve the cardiovascular system: cardiac conduction disturbances and myocardial depression, particularly in cases of overdose (Swanson et al., 1997). Before initiation of therapy with a TCA, a thorough cardiac history (e.g., palpitations, syncope) and family cardiac history (e.g., arrhythmias, sudden cardiac death) should be obtained with a baseline electrocardiogram to rule out a prolonged QT interval if history or physical examination raises suspicion. In an assessment of 64 trials in a Cochrane review covering the effects of tricyclic and related drugs in the treatment of enuresis, Caldwell et al. concluded that there was evidence for the effectiveness of TCAs in reducing the number of wet nights, but the effect was not sustained after treatment ceased. Combination of tricyclics and anticholinergics may also be more effective than monotherapy with tricyclics. Common side effects of dizziness, headache, mood changes, gastrointestinal discomfort, and neutropenia were observed (Caldwell et al., 2016).

Uses

The tricyclic antidepressants (TCAs) are primarily used in the treatment of mood disorders such as major depression, dysthymia, and bipolar disorder. They are also effective in the treatment of a broad spectrum of medical disorders, including anxiety, social phobia, obsessive–compulsive disorder, panic disorder, post-traumatic stress disorder, body dysmorphic disorder, borderline personality disorder, attention-deficit hyperactivity disorder, eating disorders such as anorexia nervosa and bulimia nervosa, as well as fibromyalgia, neuralgia, trichotillomania, insomnia, narcolepsy, chronic pain, migraine, nocturnal enuresis, Tourette syndrome, irritable bowel syndrome, smoking cessation, and ciguatera poisoning, and as an adjunct in schizophrenia.

ADVERSE EFFECTS

The adverse effects of TCAs are directly related to their effect on muscarinic, histaminic, and alpha-1 receptors, with increasing incidence directly linked to the binding affinity to these receptors. Table 22-5 shows the relative frequency of the adverse effects discussed next for each agent.

Tricyclic Antidepressants

TCAs are thought to provide relief for neuropathic pain via the serotonergic and noradrenergic pathways, perhaps due to their stabilization effects on nerve membranes.19 Although both pathways are involved in TCAs, the ratio of serotonergic to noradrenergic action may differ based on the individual medication. In vitro, TCAs demonstrate a mostly balanced inhibition of both serotonin and noradrenalin reuptake; in vivo, they are metabolized to secondary amines that primarily affect noradrenalin reuptake.20 Neuropathic pain relief with TCAs appears to occur independently of any antidepressant effect they may also produce.21 This is important to note because although the antidepressant effects of TCAs may take several weeks to develop, improvement of pain may occur substantially sooner. Titration of TCAs to an effective dose with tolerable side effects may take several weeks to achieve and require periodic reevaluation.

Toxicokinetics

The tricyclic antidepressants are well absorbed following oral ingestion. Large ingestions will be more slowly absorbed because of the anticholinergic effects and resulting decreased gut motility. There is extensive first-pass metabolism that limits oral bioavailability.

Tricyclic antidepressants are highly lipid soluble and bind extensively to tissue and plasma proteins. The volume of distribution ranges from 10 to 50 l Kg−1.

The half-life of various tricyclic antidepressants ranges from 10 to 50 h. Less than 5% of these drugs appear unchanged in the urine.

The tricyclic antidepressants are extensively metabolized by the liver and partially enterohepatically recirculated. They undergo demethylation, hydroxylation, and glucuronide conjugation. The demethylated metabolites of the tertiary amine tricyclic antidepressants are pharmacologically active. Drugs that induce hepatic microsomal enzymes speed the metabolism of tricyclic antidepressants.

Tricyclic antidepressants

Tricyclic antidepressants have been shown to impair psychomotor function, motor coordination, and open-road driving. Common side-effects of tricyclic antidepressants that may impair driving performance include sedation, blurred vision, orthostatic hypotension, tremor, excitement, and heart palpitation. Studies have indicated an increase in the risk of drivers involved in motor vehicle crashes who take tricyclic antidepressants. Tricyclic antidepressants should be avoided in individuals who wish to continue driving. If nonimpairing alternatives are not available, the physician should advise patients of the potential side-effects and recommend temporary driving cessation during the initial phase of medication initiation/dosage adjustment.