Antidepressants disadvantages

The excellent clinical efficacy of the TCAs has been well documented and the pharmacokinetic profiles are favourable. The most serious disadvantage of the TCAs lies in their cardiotoxicity. Thus, with the exception of lofepramine, all the tricyclic antidepressants, including maprotiline, block the fast sodium channels in the heart which can lead to heart block and death. Approximately 15% of all patients with major depression die by suicide and a high proportion of these (up to 25%) do so by taking an overdose of TCAs. Such a dose can be as low as 5-10 times the recommended daily dose. 

Treatment with SSRIs is started at or near their therapeutic antidepressant doses. The most significant disadvantage of these medications is a high incidence of treatment-emergent sexual dysfunction (see Sexual Dysfunction subsection later in this section), which often persists for as long as the patient continues taking the medication. 

Disadvantages of nefazodone include the need for a twice-a-day dosing schedule and dose adjustment. Work is under way to develop a once-a-day sustained release version of nefazodone. The fact that nefazodone must be started at a lower than usually effective dose and then adjusted to an effective dose is a distinct disadvantage. That is made even more problematic because arguably more variability exists among patients in terms of the optimal dose of nefazodone as far as efficacy and tolerability than for virtually any other antidepressant. Finally, nefazodone produces substantial inhibition of CYP 3A3/4, leading to the potential for adverse pharmacokinetic interactions as well as possible unknown long-term consequences. 

The approval of mirtazapine in the United States was based on six double-blind, placebo- and amitriptyline-controlled studies in which it was found to be superior to placebo and comparable with amitriptyline in terms of antidepressant efficacy (173,174). In a double-blind, crossover study, 63% of patients who failed to respond to 6 weeks of double-blind treatment with amitriptyline responded to mirtazapine (175). In two studies, mirtazapine was found to be efficacious in the treatment of patients hospitalized for major depression. In the first study, the antidepressant efficacy of mirtazapine was comparable with that of amitriptyline and superior to placebo (176). In the other study, the antidepressant efficacy was superior to that of fluoxetine (118). There are advantages and disadvantages to mirtazapine, including the following ... 

Disadvantages of the benzodiazepines include the risk of dependence, depression of central nervous system functions, and amnestic effects. In addition, the benzodiazepines exert additive central nervous system depression when administered with other drugs, including ethanol. The patient should be warned of this possibility to avoid impairment of performance of any task requiring mental alertness and motor coordination. In the treatment of generalized anxiety disorders and certain phobias, newer antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), are now considered by many authorities to be drugs of first choice (see Chapter 30). 

In the learned helpless model, animals (usually rats) are subjected to a brief (l-2h) inescapable shock. Subsequently, they are tested in a task in w hich they can terminate the shock by an operant response. Animals w ith prior inescapable shock exposure do not perform as w ell in the test (Maier and Watkins, 2005). Advantages of the learned helplessness model include its use in studies of neurochemical changes, and that it responds to repeated, rather than acute, antidepressant drug adminish ation. Disadvantages of the model include its dependence on acute stress adminish ation, suggesting it may better model posthau-madc stress disorder than major depressive disorder. 

Another difference between the SSRI antidepressants is their half-lives. Paroxetine has a half-life of approximately one day, sertraline one to two days, and fluoxetine seven to ten days. A long half-life is an advantage in maintaining a stable blood level but a disadvantage when starting or stopping the mediciaton. It takes six weeks to reach a steady state with fluoxetine. 

There seems to be no reason for avoiding the concurrent use of benzodiazepines and tricyclics although the advantages and disadvantages remain the subject of debate. Other combinations of tricyclic antidepressants and benzodiazepines would not be expected to behave differently from those described here. Some patients will possibly experience increased drowsiness and inattention with the more sedative antidepressants such as amitriptyline, particularly during the first few days, and this may be exaggerated by benzodiazepines such as diazepam. Driving risks may therefore be increased. 

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