Therapeutic dose, of SSRIs

The serotonin syndrome can occur with therapeutic doses of SSRIs (see above), but it occurs most commonly when SSRIs are co-administered with other drugs that also potentiate serotonin function. Recent case reports have suggested that there is a risk of the serotonin syndrome when SSRIs are combined with buspirone (99). 

It is perhaps not surprising that, even after taking into account pharmacokinetic differences between these drugs, the therapeutic doses of the SSRIs do not parallel their Ki for inhibition of 5-HT reuptake. For instance, citalopram is about a thousand times more selective than fluoxetine for inhibition of 5-HT uptake, and yet their clinically effective doses are similar. In short, not only is their selectivity for the 5-HT transporter in vitro a poor predictor of their efficacy in vivo but it has to be questioned whether any of these compounds actually work by blocking 5-HT uptake alone. 

Although similarities exist between the treatment of OCD with SSRIs and the treatment of depression with SSRIs, there are also some important differences. In general, doses of SSRIs for treating OCD are greater than doses for treating depression. Also, the onset of therapeutic effects may be even more delayed in OCD (6 to 12 weeks or longer) than in depression (4 to 8 weeks) following SSRI administration (Table 9-5). 

Treatment with serotonin-potentiating drugs in usual therapeutic doses can sometimes produce the serotonin syndrome. There are also case reports of this reaction with single doses of SSRIs (see also the monograph on Sertraline) (14). 

A more pressing issue surrounding SSRI use is when to stop treatment. While the therapeutic results last for some time after the end of SSRI treatment, most patients will relapse into a depressive state. Clinicians usually try to taper off the dose of SSRI in order to let the body get used to a different modulation of neurochemistry. Complete withdrawal is cautioned against since there have been reports of SSRI withdrawal effect. This effect is characterized by dizziness, fatigue, feelings of vagueness, and tension. 

The starting dose is the usual therapeutic dose for most of the SSRIs, duloxetine, and mirtazapine, whereas there is usually need for at least some upward titration of venlafaxine, bupropion,... 

To overcome these side effects, buspirone has to be gradually titrated for several days or weeks until it reaches the therapeutic dose, taking weeks for the drug to be effective and not always reaching a fully effective dose. Its short half-life in humans necessitates three-times a day (tid) dosage, which also makes it less attractive compared to the once a day dosage of SSRIs. 

Monoamine Oxidase Inhibitors (MAOIs). Shortly after their introduction, MAOIs, snch as phenelzine (Nardil), were found to reduce the frequency of panic attacks. It became a standard treatment for what is now known as panic disorder nntil snpplanted by the benzodiazepines and SSRIs. Although all MAOIs are presumably effective for panic disorder, phenelzine is the best studied and has been shown to be effective at daily doses ranging from 45 to 90 mg. When used to treat panic disorder, phenelzine should be initiated at a dose of 15mg/day and gradually increased in 15 mg increments until reaching a therapeutic dose. 

SSRls. SSRI antidepressants have also received considerable scrutiny in the treatment of OCD. Fluoxetine, fluvoxamine, paroxetine, and sertraline are all approved by the FDA for the treatment of OCD. Current studies suggest that each of these medications is more effective for OCD when administered at the higher end of the therapeutic dose range, that is, fluoxetine 60-80 mg/day, fluvoxamine 200-300 mg/ day, paroxetine 40-60 mg/day, and sertraline 150-200 mg/day. No controlled studies are yet available regarding the use of citalopram or escitalopram for OCD. Refer to Chapter 3 for more information regarding SSRl antidepressants. 

Milnacipran is also a dual-action antidepressant which, like venlafaxine, has been shown to be more effective than the SSRIs in the treatment of severe, hospitalized and suicidally depressed patients. At lower therapeutic doses, milnacipran blocks the noradrenaline transporters and therefore resembles the NRI antidepressants. Higher doses result in the serotonergic component becoming apparent (i.e. an SSRI-like action). The main problem with milnacipram appears to be its lack of linear kinetics with some evidence that it has a U-shaped dose-response curve (Figure 7.3). 

In general, SSRI doses of 50 to 75 times the common daily doses result in minor symptoms. Higher doses cause serious symptoms of seizure, arrhythmias, and decreased consciousness only doses greater than 150 times the common daily therapeutic dose can result in death (Barbey and Roose, 1998). Overdose in combination with alcohol or other drugs increases toxicity and accounts for most fatalities involving the SSRIs. Nevertheless, compared to TCA medications, which annually results in 100 to 150 fatal overdoses reported to the American Association of Poison Control Centers (AAPCC), the SSRI agents accounted for only 16 fatal overdoses reported to that organization between 1987 and 1996 (Barbey and Roose, 1998). 

Trazodone has been used therapeutically, but because of low potency and marked sedative effects, its use has been mostly restricted to a sleeping aid in doses of 50-100 mg at bedtime. It has been routinely used in adults on SSRIs, who develop sleep problems. The concern about priapism even at low doses may reduce enthusiasm for its use in male children and adolescents. 

The commonly used classes of antidepressants are discussed in the following sections, and information about doses and half-lives is summarized in Table 2-1. The antidepressant classes are based on similarity of receptor effects and side effects. All are effective against depression when administered in therapeutic doses. The choice of antidepressant medication is based on the patient s psychiatric symptoms, his or her history of treatment response, family members history of response, medication side-effect profiles, and comorbid disorders (Tables 2-2 and 2-3). In general, SSRIs and the other newer antidepressants are better tolerated and safer than TCAs and MAOIs, although many patients benefit from treatment with these older drugs. In the following sections, clinically relevant information is presented for the antidepressant medication classes individually, and the pharmacological treatment of depression is also discussed. The use of antidepressants to treat anxiety disorders is addressed in Chapter 3. 

All of the SSRIs also show a flat dose-response curve, meaning that there is usually no advantage to increasing the dose above that which is the usually effective minimum dose. Of interest, the four SSRIs marketed as antidepressants in the United States at their usual effective therapeutic dose (i.e., 40 mg per day for citalopram, 20 mg per day for paroxetine and fluoxetine, and 50 mg per day for sertraline) produce comparable effects on either plasma serotonin levels or the serotonin uptake pump in platelets (25). These results are consistent with the conclusion that serotonin uptake inhibition is the mechanism responsible for the antidepressant efficacy of these agents. 

Nevertheless, there is wide interindividual variability in the metabolism of SSRIs, comparable with that of TCAs. Therefore, some patients who rapidly or slowly clear these drugs may need a higher or lower dose, respectively, than the usually effective dose. This issue is further addressed in the section on therapeutic drug monitoring later in this chapter. 

Optimal dosing with venlafaxine differs from that of both TCAs and SSRIs. Venlafaxine is like the SSRIs and different from the TCAs in that a therapeutic dose (i.e., 75 mg per day) can be started from the beginning. Unlike the SSRIs, however, dose escalation with venlafaxine does increase the magnitude of the antidepressant effect, which supports increasing the dose in the event of an inadequate response to the initial trial ( Table 7-9). Venlafaxine in its sustained release formulation can be given once a day, just like the SSRIs and TCAs. 

Given the wide therapeutic index of the SSRIs, the safety issues that make TDM a standard of care with the TCAs are not applicable to this class. Although the risk and severity of their typical adverse effects (e.g., nausea) increase with dose escalation, there is almost no chance of life-threatening toxicity. Hence, physicians can adjust the dose of these drugs upward without this concern. The issue of TDM with the SSRIs, therefore, involves increasing the percentage of patients who will experience an optimal antidepressant response. 

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... 

Drug combinations Probably the most common combination treatment is concomitant use of an SSRI and a benzodiazepine, especially on initiation of treatment (Fig. 9—6). The benzodiazepines (especially alprazolam and clonazepam) not only appear to act synergistically to increase the onset of therapeutic action and perhaps even boost the efficacy of SSRIs, but they also appear to block the anxiogenic actions of the SSRIs and lead to better tolerability as well as the ability to attain therapeutic dosing levels for the SSRIs. Sometimes sedative-hypnotics such as zale-plon or zolpidem are required in addition to an SSRI, especially on initiation of SSRI treatment. 

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