Enuresis tricyclic antidepressants

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. 

Both accidental and intentional overdose are relatively frequent and pose difficult management problems. Particular concern has been expressed for children, either because they gain access to parents tablets or have been treated for enuresis. During one year a Melbourne hospital admitted 35 children poisoned with tricyclic antidepressants (147). In 1979 it was reported that tricyclic antidepressants had replaced salicylates as the most common cause of accidental death in English children under the age of five. Concern was expressed about this (148), and Swiss federal statistics raised similar worries (149). 

Tricyclic antidepressants are used to treat depression. They are also used for treatment of enuresis in children, chronic pain syndromes, neuropathic pain, the fibromyalgia syndrome, and chronic headaches. 

Tricyclic antidepressants represent a class of drugs widely prescribed for the treatment of endogenous depression and neuralgic pain, migraine headache, enuresis, and attention deficit disorder (see Chapter 33). Tricyclic antidepressants include imipramine, amitriptyline, and their N-... 

Tofranil imipramine tricyclic antidepressant ADHD, eating disorders, enuresis, depression sedation, dry mouth, changes in blood pressure, constipation... 

OTHER THERAPEUTIC USES OE THESE DRUGS The various antidepressant agents have found broad utility in other disorders that may not be related psychobiologicaUy to the mood disorders. Current applications include rapid but temporary suppression of enuresis with low (e.g., 25 mg) pre-bedtime doses of tricyclic antidepressants, including imipramine and nortriptyline, by uncertain mechanisms in children and in geriatric patients, as well as a beneficial effect of duloxetine on urinary stress incontinence. Antidepressants have a growing role in attention-deficit/hyperactivity disorder in children and adults, for which imipramine, desipramine, and nortriptyline appear to be effective, even in patients responding poorly to or who are intolerant of the stimulants (e.g., methylphenidate). Newer NE selective reuptake inhibitors also may be useful in this disorder atomoxetine is approved for this application. Utility of SSRIs in this syndrome is not established, and bupropion, despite its similarity to stimulants, appears to have limited efficacy. 

Enuresis is an established indication for tricyclics. Chronic pain states, which may be unresponsive to conventional analgesics, sometimes respond to tricyclic antidepressants. The answer is (C). 

The addition of liothyronine 25 micrograms daily was found to increase the speed and efficacy of imipramine in relieving depression. Similar results have been described in other studies with desipramine or amitriptyline but the reasons are not understood. One possible explanation is that the patients had overt or subclinical hypothyroidism, which after correction with liothyronine allowed them to overcome an impaired response to tricyclic antidepressants." However, adverse reactions have also been seen. A patient being treated for both hypothyroidism and depression with thyroid 60 mg and imipramine 150 mg daily complained of dizziness and nausea. She was found to have developed paroxysmal atrial tachycardia. A 10-year-old girl with congenital hypothyroidism, well controlled on desiccated thyroid 150 mg daily, developed severe thyrotoxicosis after taking imipramine 25 mg daily for 5 months for enuresis. The problem disappeared when the imipramine was withdrawn. In another patient the effect of levothyroxine was lost and hypothyroidism developed when dosulepin was started. ... 

In addition to the treatment of depression, the Food and Drug Administration (FDA) has approved the (on-label) use of the antidepressants for treatment of panic disorders, obsessive-compulsive disorders, bulimia nervosa, social phobia, and generalized anxiety disorder. And although not the treatment of choice, the tricyclics are sometimes used for enuresis—bed wetting. 

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