Tricyclic antidepressants nocturnal enuresis

Mechanism of Action A tricyclic antidepressant that blocks the reuptake of neu-rotransmitters, such as norepinephrine and serotonin, at presynaptic membranes, in-creasing their concentration at postsynaptic receptor sites. Therapeutic Effect Results in antidepressant effect. Anticholinergic effect controls nocturnal enuresis, Pharmacohinetics Rapidly, completely absorbed after PO administration, and not affected by food. Protein binding 95%, Metabolized in liver (significant first-pass effect), Primarily excreted in urine. Not removed by hemodialysis. Half-life 16-40 hr. 

Tricyclic antidepressants have been used for decades to treat depression and anxiety in the general population, and clomipramine has been used to treat OCD. Clomipramine has been studied with respect to treating school phobia or school refusal (Berney et ah, 1981). Gittleman-Klein and Klein (1971) found imipramine to be superior to placebo in treating school refusal. As the TCAs may improve other disorders such as nocturnal enuresis, ADHD, and sleep disorders, they may be attractive for children with any of these comorbid conditions and anxiety disorder. 

FIGURE 51.3 Paradigm for pure nocturnal enuresis intervention. TCAs, tricyclic antidepressants. 

The efficacy of imipramine has been repeatedly demonstrated in controlled trials about 85% of children treated within a week of the start of medication, but tolerance frequently develops after a number of weeks and relapse is high after discontinuation of the treatment. Relatively low doses of imipramine only are needed, but the typical side effects of tricyclic antidepressants limit the prolonged use of the drug. The mechanism of action of imipramine in the treatment of nocturnal enuresis is unclear but one possible action is through a direct anticholinergic action on the bladder wall. 

The synthetic vasopressin peptide, desmopressin, has been extensively investigated and shown to be effective as tricyclic antidepressants in the control of nocturnal enuresis and to enhace the enuretic night alarm treatment. The side effects are relatively few (nasal pain, conjunctivitis) when given by nasal spray. The precise mechanism of action of this peptide is unknown. 

Although pediatric psychopharmacology is much neglected, nocturnal enuresis is an area of extensive research. An earlier review catalogued almost 100 publications on the topic (13). The tricyclic antidepressants have been shown to be effective in well-controlled trials, and over 40 publications had appeared before 1970. At that time adverse effects in children appeared to be minimal and comparable to those in adults. Since then considerable concern has developed over cardiotoxic effects and the risks of accidental overdose in children. The earlier reports have been summarized (SEDA-1,10) managing overdose in children has been reviewed (SEDA-2,10) death in a 16-month-old infant has been reported (SEDA-3, 9). 

Several organs are the target for the anticholinergic (anti-muscarinic) activity of the tricyclic antidepressants. They constitute the most common and troublesome adverse effects of the tricyclic antidepressants, but the peripheral anticholinergic actions can also be put to therapeutic use in conditions such as irritable bowel syndrome, premature ejaculation, and nocturnal enuresis. 

The tricyclic antidepressants increase bladder sphincter tone and the volume of fluid necessary to trigger detrusor contraction (80). Such effects may account for their efficacy in nocturnal enuresis, in which the benefit occurs early and at a low dosage, consistent with anticholinergic activity. However, this pharmacological action can cause hesitancy and urinary retention, especially in predisposed men who have prostatic hyperplasia. 

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