Half-life antidepressants

Several reports have described a series of symptoms after discontinuation or dose reduction of serotonergic antidepressant medications. The most common symptoms include dizziness, headache, paresthesia, nausea, diarrhea, insomnia, and irritability. Of note, these symptoms may also be seen when a patient misses doses. A prospective, double-blind, placebo-substitution study confirmed that discontinuation symptoms are most common with short half-life antidepressants, such as paroxetine (Rosenbaum et al. 1998). 

When switching between a MAOl and other antidepressants that affects serotonin activity, the first medication must be allowed to wash out of the patient s system before the new antidepressant is started. The duration of this washout period is determined by the half-life of the antidepressant that is being discontinued. If a washout is neglected, then a potentially dangerous serotonin syndrome may result. 

In general, the lowest effective dose of the drug should be used, particularly in elderly patients. Dose titration should be undertaken slowly. Similarly, on discontinuation of a drug, the dose should be reduced slowly, the rate of decrease being decided by the elimination half-life of the drug. Some psychotropic drugs produce a discontinuation syndrome that can usually be avoided by slow withdrawal. In particular, sedatives, anxiolytics and antidepressants can cause withdrawal effects. 

Changing a patient from one MAOI to another, or to a TCA, requires a "wash-out" period of at least 2 weeks to avoid the possibility of a drug interaction. There is evidence to suggest that a combination of an MAOI with clomipramine is more likely to produce serious adverse effects than occurs with other TCAs. Regarding the newer non-tricyclic antidepressants, it is recommended that a "wash-out" period of at least 5 weeks be given before a patient on fluoxetine is given an MAOI this is due to the very long half-life of the main fluoxetine metabolite norfluoxetine. 

Mechanism of Action An antidepressant that appears to inhibit serotonin and norepinephrine reuptake at CNS neuronal presynaptic membranes is a less potent inhibitor of dopamine reuptake. Therapeutic Effect Relieves depression. Pharmacokinetics Well absorbed from the G1 tract. Protein binding greater than 90%. Extensively metabolized to active metabolites. Excreted primarily in urine and, to a lesser extent, in feces. Half-life 8-17 hr. 

Mechanism of Action A tetracyclic compound that blocks reuptake norepi nephri ne by CNS presynaptic neuronal membranes, increasing availability at postsynaptic neuronal receptor sites, and enhances synaptic activity. Therapeutic Effect Produces antidepressant effect, with prominent sedative effects and low anticholinergic activity. Pharmacokinetics Slowly and completely absorbed after PO administration. Protein binding 88%. Metabolized in liver by hydroxylation and oxidative modification. Excreted in urine. Unknown if removed by hemodialysis. Half-life 27-58 hr. 

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 (TCAs) modulate various brain neurotransmitters, especially norepinephrine and serotonin, by blocking reuptake presynaptically. The secondary amines (desipramine, nortriptyline) are more selective for noradrenergic function and have less side effects in sensitive populations. Advantages of this class of drugs include their relative long half life (approximately 12 hours), absence of abuse potential, and putative positive effects on mood and anxiety, sleep, and tics. 

Milnadpran is a rather newer SNRI licensed as an antidepressant in France. It is associated with clear-cut efficacy judged on the placebo-controlled studies [Lecrubier et al. 1996 Macher et al. 1989]. Milnacipran inhibits the reuptake of both noradrenaline and serotonin (Moret et al. 1985]. It has a relatively short half-life and is given optimally in a dose of 50 mg twice daily. The proportion of reuptake inhibition between serotonin and noradrenaline is approximately equal with this antidepressant, and so one would expect that milnacipran would be more effective than SSRIs, assuming the theory is correct that two actions are better than one. 

Particular care must be exercised when switching from an MAOI to other antidepressant classes. In patients who have completed an MAOI trial without achieving a therapeutic response, treatment with other antidepressants should not be started until 14 days after discontinuation of the original MAOI. Equal care is required when switching from most other antidepressants to an MAOI. An interval equal to five times the half-life of the drug, including active metabolites, is required between stopping treatment with other antide-... 

Buspirone may be an effective anxiolytic in the elderly patient and less likely than BZDs to produce excessive sedation ( 352, 353, 354 and 355). Dizziness, however, may be a problem. Zolpidem or zaleplon, particularly in lower doses (i.e., 2.5 to 5.0 mg at bedtime) may be viable alternatives ( 356). The elimination half-life of these two agents is approximately 3 hours in the elderly. Although it has sleep-enhancing properties similar to BZD hypnotics, it is less likely to alter sleep architecture. Whereas antidepressants and b -blockers may be useful alternatives in younger patients, no data document their effectiveness for anxiety in elderly patients ( 307). Although antipsychotics may be helpful in reducing severe agitation, their side effect profile makes them unsuitable for use in subjective anxiety states ( 300, 307). 

The tricyclic antidepressants are all lipid-soluble, are well absorbed from the gut, and are widely distributed in the body. Peak plasma levels are reached 2-6 hours after a single oral dose and elimination half-life is between 8 hours and 36 hours, generally allowing once-daily dosing. Most have active metabolites, also with relatively long half-lives. They are highly bound to plasma proteins (75-95%) and undergo extensive hepatic metabolism. 

Oral contraceptives reduce the clearance of imipramine, probably by reducing hepatic oxidation, and thus increase its half-life. Hydroxylation of amitriptyline is inhibited by contraceptive steroids. The clinical significance is uncertain, but there is at least anecdotal evidence of an increase in antidepressant adverse effects (360). Caution should be exercised when tricyclic antidepressants are used long term in women taking oral contraceptives. 

Maprotiline, a tetracyclic antidepressant, repeatedly induced hypoglycemia in a 39-year-old woman with type 1 diabetes, even when the insulin dosage was reduced from 20 U/day to 4-10 U/day. Maprotiline seems to prolong the half-life of insulin. A glucagon... 

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