Antidepressants: The Formulation of Treatment

The Formulation of Treatment

Indications

All antidepressants are indicated for the treatment of acute ma-jor depressive episodes. Beyond the acute period, there is also evidence for the use of antidepressants in the prevention of re-lapse and recurrence.

There are a number of more minor forms of depression, many of which may also respond to antidepressant medication. Best studied of these is dysthymic disorder. Previously thought to be unresponsive to somatic therapy, a growing literature at-tests to the responsiveness of this chronic, minor depressive disorder to a variety of medications, including TCAs (Kocsis et al., 1985; Stewart et al., 1993) and serotonin reuptake inhibi-tors (Hellerstein et al., 1993; Thase et al., 1996; Ravindran et al., 1994; Vanelle, 1997). As with major depression, there is no de-finitive data to suggest that any one agent is more efficacious than the other. The bulk of data suggests, instead, that any available agent used for major depression is likely to be effective for these other disorders.

Other minor depressive disorders include minor depres-sion and recurrent brief depression. Though rigorous data is largely lacking in the treatment of these disorders, they seem to show an at least modest response to antidepressant medications.

Other Uses for Antidepressants

Although we will describe the use of anti-depressants in the treatment of major depression, they are also used to treat a number of other conditions (Orsulak and Waller, 1989; Brotman, 1993). Some uses have gained general accept-ance while other uses rely on moderate or preliminary evidence. A summary of various indications is presented in Table 79.2.

Selection of an Antidepressant

The decision whether to treat depressive symptoms with phar-macotherapy requires an assessment of both the need for in-tervention and the likelihood that treatment will be successful. Assessing the need for intervention involves longitudinal and cross-sectional factors. Assessing the likelihood that treatment will be successful is somewhat more difficult, but may rely on clinical, demographical and biological factors.

Assessing the Need for Intervention

This involves assessing the likely result if pharmacological treat-ment is not given. It is essential in making a useful risk–benefit assessment.

Longitudinal Factors The physician should consider the course and duration of previous episodes of depression. Such episodes can predict the potential severity of the current episode, the likely time to recovery, and the probability of a subsequent recurrence. The physician should also consider the likely complications of depression for the individual patient, which may include sub-stance abuse and suicide.

Cross-sectional Factors The physician should consider the severity of symptoms and the degree of functional impairment. Suicidal ideation is of particular concern and needs rapid and in-tensive treatment. Such treatment often includes hospitalization. Even with less pressing symptoms, but significant occupational or social impairment, the risk–benefit ratio generally still favors a trial of antidepressants, particularly now that safer and more easily tolerated agents are available.

Selection of a Particular Agent Although, as noted earlier, the various antidepressants seem to have equal efficacy in the treat-ment of depression, a given patient may respond preferentially to one, or a class of agents. Again, cross-sectional and longitudinal factors should be taken into account.

Pharmacokinetic Concerns

First-generation Antidepressants The pharmacokinetics of TCAs is complex. This complexity is reflected in the diversity of half-lives reported, which vary roughly from 10 to 40 hours. TCAs are primarily absorbed in the small intestine. They are usually well absorbed, and reach peak plasma levels 2 to 6 hours

after oral administration. Absorption can be affected by changes in gut motility. The drugs are extensively metabolized in the liver on first pass through the portal system. They are lipophilic, have a large volume of distribution and are highly protein-bound (85–95%). TCAs are metabolized in the liver by hepatic micro-somal enzymes, by demethylation, oxidation, or hydroxylation. They are generally metabolized to active metabolites, and are excreted by the kidneys. There is a large range of elimination half-lives among the antidepressants.

MAOIs are also well absorbed from the gastrointestinal tract. Their metabolism, although quite efficient (they have a half-life of 1 to 2 hours), is not well understood. The short half-life of these compounds is not entirely relevant however, as they bind irreversibly with MAO. Thus, the activity of these drugs depends less on pharmacokinetics, and more on the synthesis of new MAO to restore normal enzyme activity. This synthesis re-quires approximately 2 weeks.

Second-generation Antidepressants All of the available serot-onin reuptake inhibitors are well absorbed, and not generally af-fected by food administration. Sertraline is an exception to this rule, and its blood level may be increased by food. All serotonin reuptake inhibitors have large volumes of distribution and they are extensively protein-bound. They are metabolized by hepatic microsomal enzymes and are potent inhibitors of these enzymes (a fact which will be discussed later in greater detail).

The only serotonin reuptake inhibitor with an active me-tabolite is fluoxetine, whose metabolite norfluoxetine has a half-life of 7 to 15 days. Thus, it may take several months to achieve steady state with fluoxetine. This is considerably longer than cita-lopram, which has a half-life of about 1.5 days, or sertraline and paroxetine, which have half-lives of about a day.

As previously discussed, there is no correlation between half-life and time to onset. Drugs with shorter half-lives have an advantage in cases where rapid elimination is desired (for exam-ple, in the case of an allergic reaction). Drugs with a longer half-life may also have advantages: fluoxetine, for example, has been successfully given in a once-weekly dosing during the continu-ation phase of treatment (Burke et al., 2000), and a once-weekly formulation of this drug is currently available. All serotonin reuptake inhibitors are eliminated in the urine as inactive me-tabolites. Both fluoxetine and paroxetine are capable of inhibiting their own clearance at clinically relevant doses. As such, they have nonlinear pharmacokinetics: changes in dose can produce proportionately large plasma levels.

As with most of the other antidepressants, bupropion un-dergoes extensive first pass metabolism in the liver. Although the parent compound has a half-life of 10 to 12 hours, it has three me-tabolites that appear to be active. One, threohydrobupropion, has a half-life of 35 hours and is relatively free in plasma (it is only 50% protein-bound). There is considerable individual variability in the levels of bupropion and its metabolites. Trazodone has a half-life that is relatively short, having a range of 3 to 9 hours. Given this, and its apparent lack of active metabolites, the plasma levels of trazodone can be quite variable during a day. For this reason, the medication requires divided dosing.

Third-generation Antidepressants Venlafaxine has a short half-life (4 hours); however, it is available in an extended release formulation that allows once-daily dosing. It appears to have a dual effect, in which at lower doses it primarily acts on the serotonin transporter, and clinically significant norepinephrine reuptake inhibition is not seen until higher doses are used (150 mg/day and above).

Nefazodone has relatively low bioavailability, and a short half-life (2–8 hours), and thus it is usually given in twice-daily doses. Mirtazapine has a half-life of 13 to 34 hours.