Antidepressant agents tolerance

Antidepressant agents show almost the same degree of tolerance as to the nature of the tricyclic moiety as do the antipsychotic agents. Thus the dehydration product(s) from the condensation of ketone 9 with the Grignard reagent from 3-chloroethyl-N, J -dimethylamine affords the antidepressant diothiepin (98). ... 

For whatever reason, few controlled trials of antidepressants have been performed in the treatment of dysthymic disorder. The limited evidence available, however, suggests that the same classes of antidepressants that effectively treat major depression also treat dysthymia. Reported side effects are similar with the newer agents tolerated better than TCAs. 

With the introduction of the SSRIs, the safety and tolerability of antidepressants improved remarkably. As a class, these medications have little or no affinity for cholinergic, (3-adrenergic or histamine receptors and do not interfere with cardiac conduction. They are well tolerated by patients with heart disease and by the elderly, who are especially sensitive to the anticholinergic and orthostatic effects of the tricyclic antidepressant agents (TCAs) and monoamine oxidase inhibitors (MAOIs). 

When evaluating response to an antidepressant agent, in addition to target signs and symptoms, consider quality-of-life issues such as role, social functioning, and occupational function. In addition, the tolerability of the agent should be assessed because the occurrence of side effects may lead to nonadherence to the regimen. 

Amphetamine Clinically used for narcolepsy (sudden day-time onset sleep) and Attention Deficit Hyperactivity Disorder (ADHD) formerly used as a short-term slimming agent, as an antidepressant and to boost athletic performance recreational use widespread tolerance develops readily highly addictive regular users suffer many health problems and a reduced life expectancy amphetamine psychosis may develop, with similar symptoms to acute paranoid schizophrenia. 

The selective serotonin reuptake inhibitors (SSRIs) inhibit the reuptake of 5-HT into the presynaptic neuron. They are generally chosen as first-line antidepressants because of their safety in overdose and improved tolerability compared to earlier agents. 

We do not use benzodiazepines as readily when treating GAD as we do when treating panic disorder. In comparison to those with panic disorder, most patients with GAD can more easily tolerate the delay in treatment response and even any transient exacerbation of anxiety associated with antidepressant therapy. Benzodiazepines are reserved for those who present with especially severe anxiety that necessitates more rapid relief than an antidepressant can afford and for those who do not achieve a satisfactory response to antidepressant or buspirone therapy. Due to the persistent nature of the anxiety experienced by patients with GAD, shortacting benzodiazepines such as alprazolam are not especially helpful unless dosed 3-4 times per day. Instead, we prefer long-acting agents such as clonazepam. When used to treat GAD, clonazepam should be started at a low dose (0.25-0.5 mg/day) and titrated to higher doses (1-4 mg/day) if clinically necessary. 

C. All agents have a delay of approximately 48 hours. There are no signihcant differences in efficacy among the individual agents. The major contribution of the newer antidepressants is in their improved safety and tolerability. 

In this chapter, we review the pharmacology of several selective serotonin reuptake inhibitors [SSRIs] and other drugs that act on the serotonergic system. That these developments have enhanced safety and tolerability is now beyond dispute, but it is also clear that these agents are no more effective than the old-style tricyclic antidepressants [TCAs]. [For a comprehensive discussion of serotonergic medication, see Montgomery, Chapter 12, in this volume.] Here, several compounds are discussed in detail. 

Because of the improved tolerability and safety of newer antidepressants, MAOIs are not currently used as first-line agents. However, MAOIs remain excellent medications for patients whose symptoms do not respond to the newer antidepressant drugs. Patients with atypical depression, characterized by oversleeping and overeating, show a preferential response to MAOI therapy compared with TCAs (Liebowitz et al. 1984 Quitkin et al. 1979 Ra-varis etal. 1980 Zisook 1985). 

An important aspect of antidepressant pharmacotherapy is selection based on the adverse effect profile of a specific medication, because most antidepressants are comparable in terms of efficacy. One of the major accomplishments of modern antidepressant development has been to improve the adverse effect profile of newer agents in comparison with TCAs and MAOIs without compromising efficacy (1). That has been accomplished by developing chemicals that retain the ability to affect sites of action that appear to be capable of mediating antidepressant efficacy (e.g., the serotonin uptake pump), but avoid effects on unnecessary sites of action (e.g., ACh receptor, fast sodium channels). This approach has led to both better tolerated and safer medications. Table 7-23 lists the common potential adverse affects of a number of antidepressants, as well as their relative severity. 

At the present time, the TCAs are used primarily in depression that is unresponsive to more commonly used antidepressants such as the SSRIs or SNRIs. Their loss of popularity stems in large part from relatively poorer tolerability compared with newer agents, to difficulty of use, and to lethality in overdose. Other uses for TCAs include the treatment of pain conditions, enuresis, and insomnia. 

At present, SSRIs are the most commonly prescribed first-line agents in the treatment of both MDD and anxiety disorders. Their popularity comes from their ease of use, tolerability, and safety in overdose. The starting dose of the SSRIs is usually the same as the therapeutic dose for most patients, and so titration may not be required. In addition, most SSRIs are now generically available and inexpensive. Other agents, including the SNRIs, bupropion, and mirtazapine, are also reasonable first-line agents for the treatment of MDD. Bupropion, mirtazapine, and nefazodone are the antidepressants with the least association with sexual side effects and are often prescribed for this reason. However, bupropion is not thought to be effective in the treatment of the anxiety disorders and may be poorly tolerated in anxious patients. The... 

Mexilitine has analgesic properties in several neuropathic pain syndromes and is an alternative agent for treatment of patients who fail to respond to tricyclic antidepressants or who cannot tolerate them... 

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