The goal behind the rational development of selective serotonin reuptake inhibitors (SSRIs) is to:

• Either maintain or ideally enhance antidepressant efficacy
• Increase the therapeutic index (ie, the safety margin between the effective versus the toxic dose)
• Improve the tolerability profile
• Reduce the risk of pharmacodynamically mediated drug-drug interactions

This development plan has succeeded relative to tricyclic antidepressants (TCAs). Hence, SSRIs, for many physicians, have replaced TCAs as antidepressants of first choice in the treatment of patients with major depression. They also have increased the likelihood that a patient with symptoms of major depression will receive a trial of an antidepressant at an optimal dose. The reason for the increased likelihood of a trial of antidepressant is that physicians are more comfortable giving an empirical trial of SSRIs than a trial of TCAs due to their wider safety margin and better tolerability. The likelihood that an optimal dose will be used is that there is no need to titrate the dose of SSRIs for most patients. The starting dose is the optimal for most patients. Dose increases, in general, serve little purpose.

TABLE 4.1 — STEPS: Factors to be Considered When Selecting a Medication for a Patient Safety – Acute therapeutic index – Long-term safety – Risk of drug-drug interactions:     • Pharmacodynamically mediated     • Pharmacokinetically mediated Tolerability – Acute – Long-term Efficacy – Overall response rate – Unique spectrum of activity in subpopulations – Rate of onset – Maintenance – Prophylactic Payment (ie, cost-effectiveness) Simplicity – Drug administration schedule – Ease of optimal dosing – Need for specific clinical or laboratory monitoring before or during treatment References: 49, 210

TABLE 4.2 — Safety and Tolerability of TCAs versus SSRIs Consideration TCAs SSRIs Safety    Overdose lethality risk    Alcohol potentiation high high low low Tolerability    Anticholingeric adverse events    Antihistimine adverse events    Anti-a1 adrenergic adverse events    Serotonin adverse events high high high low low low low high

The differences in the clinical pharmacology of TCAs versus SSRIs will be reviewed in this chapter in terms of the STEPS analysis developed by the author (Table 4.1).

Safety

Table 4.2 summarizes the clinically meaningful differences between TCAs and SSRIs in terms of safety and tolerability. Due to the fact that SSRIs do not inhibit fast sodium channels, there is essentially no risk of lethality, even with a substantial overdose of these medications. In contrast, overdoses of a TCA of as little as 5 times the daily dose can be lethal.²²⁵ This issue is important because of the delay between starting an antidepressant of any class and achieving a meaningful improvement in the depressive syndrome.

The risk of a suicide attempt is a serious concern during this delayed onset interval. For many years, TCAs have been a leading cause of death due to drug overdose because of their serious toxicity profile, coupled with the fact that they are given to patients at risk for making serious suicide attempts.^52,97,165 Because SSRIs avoid this problem, the prognosis of patients suffering from this condition has significantly improved.

It used to be axiomatic to warn patients about the dangers of drinking alcohol while taking antidepressants. While it is still wise to advise patients against drinking alcohol when clinically depressed, the reason is no longer because the antidepressant will necessarily cause serious potentiation of the central nervous system (CNS) depressant effects of alcohol and other CNS depressants such as benzodiazepines. Such potentiation occurs when TCAs and alcohol are taken together due to the antihistaminic effects of TCAs, particularly tertiary amine TCAs. Since SSRIs have been designed to avoid blocking the histamine receptor, they do not pharmacodynamically potentiate the effect of alcohol or other CNS depressants.^{76,123,155,251} Instead, they either do nothing or may mildly antagonize the depressant effects of alcohol.^{76,123,155,251} This change is just one example of the reduced risk of serious pharmacodynamic drug interactions due to the more focused pharmacology of SSRIs. Parenthetically, fluvoxamine and fluoxetine can pharmacokinetically potentiate the effects of 2-keto and triazolo benzodiazepines, such as diazepam and alprazolam respectively, by inhibiting the cytochrome P450 (CYP) enzymes responsible for their clearance (see Section 8).

The avoidance of pharmacodynamically mediated drug-drug interactions is important because of the length of time that patients may be on antidepressants to prevent relapse or recurrence of depressive illness. As discussed in Section 8, antidepressants are frequently used in combination with other drugs for a variety of reasons:

• Concomitant medical illness
• Augmentation strategies
• The addition of another drug to reduce a nuisance adverse effect (eg, cisapride to treat nausea which can occur early in SSRI treatment)

In addition, patients may drink alcohol socially while taking an antidepressant and then try to drive home. Alternatively, they may take "over-the-counter" (OTC) preparations and have an interaction (ie, taking an OTC drug that has sedative properties). If they are taking a tertiary amine TCA and drink alcohol or take such an OTC product, they may experience serious potentiation of sedative effects that may be dangerous, particularly if they are in a situation where they need to be mentally alert with good reaction time and coordination.

Due to the multiple pharmacodynamic effects of TCAs, there are multiple ways that they can interact with other types of drugs beyond simply the potentiation of CNS depressants. Since TCAs block a₁-adrenergic receptors, they lower peripheral resistance.¹⁰³ If the patient is also taking other medications that lower blood pressure (eg, diuretics, ß-blockers), they may experience a marked potentiation of the orthostatic hypotension that can occur with drugs that block a₁-adrenergic receptors, that can have serious consequences in terms of falls and resultant trauma, particularly in the elderly.²³⁶ Since SSRIs have been also designed to avoid blocking the a₁-adrenergic receptor, they do not potentiate the effects of concomitantly prescribed antihypertensive medications, in contrast to TCAs. This is another example of the reduced risk of pharmacodynamically mediated drug interactions as a result of the more focused pharmacology of SSRIs.

Since TCAs block the muscarinic acetylcholine receptor, they can have additive effects with other drugs that also block this receptor or which affect gastrointestinal tract motility through other actions. Since TCAs inhibit fast sodium channels, they can potentiate the effects of other drugs which affect intracardiac conduction. Such drugs include a variety of antiarrhythmics, calcium channel blockers, and B-blockers. SSRIs, because of their more focused pharmacology, have a much more limited range of pharmacodynamically mediated drug-drug interactions than do TCAs.

Tolerability

Another important difference between SSRIs and TCAs is a better overall tolerability profile in terms of a lower incidence of both nuisance and serious adverse effects. SSRIs affect fewer sites of action (SOAs) and hence cause fewer types of adverse effects. Table 4.3 shows the relative incidence of adverse effects on imipramine as a representative TCA. Imipramine was chosen because it has historically been and still is one of the most commonly used TCAs. Table 5.2 shows the relative incidence of the same adverse effects on 4 of the 5 SSRIs. A comparison of these 2 tables reveals that imipramine in comparison to the SSRIs is associated with a considerably higher incidence of adverse effects mediated by the blockade of specific neuroreceptors such as muscarinic acetylcholine receptors (eg, dry mouth, constipation) and a₁-adrenergic receptors (eg, dizziness). In contrast, SSRIs as a group have a higher incidence of adverse effects mediated by the indirect potentiation of serotonin via the inhibition of its uptake pump (eg, nausea). Figure 4.1 provides a visual representation of the same phenomena using amitriptyline as another representative tertiary amine TCA and sertraline as a representative SSRI.

While these adverse effects are less dramatic than the potentially life-threatening toxicity problems that can occur while taking TCAs, they can have serious consequences. The orthostatic hypotension that can occur on TCAs may cause falls with resultant trauma.²³⁶ The chronic anticholinergic effects can lead the patient to discontinue treatment during the maintenance phase of treatment and thus increase the risk of relapse. In clinical studies, the discontinuation of tertiary amine TCAs such as imipramine can be 3 times higher than the discontinuation rate on an SSRI (eg, 22% versus 7% respectively).²¹¹

FIGURE 4.1 — Comparative Incidence of Side Effects Between Amitriptyline and Sertraline Treatment-emergent side effects (all causalities) in double-blind, placebo-controlled, outpatient trial. Reference: 237

TABLE 4.4 — Response Rates in Patients With Major Depressive Disorder by Meta-analysis TCAs and SSRIs (as a class) vs. Placebo Drug Placebo Difference n p value TCAs 62.8% 35.9% 26.9% 5159 < 10 –40 SSRIs 66.5% 38.1% 28.4% 2216 < 10 –30   SSRI TCA Difference n p value TCAs vs. SSRIs 77.2 76.9 0.3% 850 NS NS = Not significant From reference: 135

Efficacy

While rational drug development reduces the risk of safety and tolerability problems with SSRIs versus TCAs, it does not reduce the relative antidepressant efficacy of the SSRIs. As a group, they are as effective as TCAs in the treatment of outpatients with major depression. This conclusion is supported by a meta-analysis of the double-blind clinical trials of TCAs and SSRIs versus placebo and the double-blind trials directly comparing the antidepressant efficacy of SSRIs and TCAs (Table 4.4). In this table, efficacy is presented as response rate on each treatment after a 6-week treatment trial. A responder is defined as a patient who experienced at least a 50% reduction in the depressive symptomatology as assessed by a standardized assessment instrument, such as the Hamilton Depression Rating Scale (HDRS).

The conclusion that TCAs and SSRIs have comparable antidepressant efficacy in this group of patients is based on the fact that they both produce overall response rates of 60% to 65% and that these rates are comparably superior to those achieved in a double-blind, parallel, placebo-treated, control group. Both the SSRIs and the TCAs produce a 25% to 30% higher response rate than placebo. This difference between drug and placebo is also statistically superior to a comparable degree.

Nonetheless, these results do not necessarily mean that exactly the same patients respond to SSRIs and TCAs. Some investigators have suggested that TCAs may work better in patients who are hospitalized for major depression.^69,70,244 That opinion is based on a few double-blind, active, controlled studies. However, this issue remains controversial and is not presently resolved. There are also studies showing that up to 50% patients who fail to respond to desipramine or a similar TCA will respond to an SSRI and vice versa.^{1,2,81,124,164,190,191}

That finding further suggests that the spectrum of antidepressant activity by these 2 classes of drugs is not identical. However, considerable work needs to be done to confirm or reject these hypotheses. Nonetheless, current data do suggest that it is clinically reasonable to give a patient who has failed on an SSRI a trial of a TCA or related drug as well as vice versa.

Payment

This topic is clearly important and is part of the STEPS analysis.⁴⁹ However, a full discussion is beyond the scope of this book, given its focus on clinical pharmacology. Nonetheless, the clinical pharmacology of SSRIs versus TCAs must be considered when analyzing the issue of payment or cost-effectiveness of these different classes of antidepressants. The acquisition cost of SSRIs is higher than that of TCAs but that is only one part of the cost-effectiveness equation. To be meaningful, a cost-effectiveness analysis must be much more comprehensive and consider such factors as:

• The cost of administering the treatment
  - Number of physician visits
  - Ancillary tests that are needed to monitor the treatment
• The cost of treating potential adverse outcomes that may range from nuisance side effects to serious toxicity such as can occur with an overdose of a TCA
• The cost of an adverse outcome due to an adverse drug-drug interaction
• The cost of effective treatment must be balanced against the cost of not effectively treating the illness (eg, loss productivity), including increased relapse rates in patients who discontinue treatment before the drug has a chance to work or who relapse because of discontinuing treatment too early because of intolerable side effects

Simplicity

Simplicity refers to how easy it is for the physician to prescribe the optimal dose and for the patient to take it. One advantage shared by both TCAs and SSRIs is that they can generally be taken once a day and be effective. Other than this shared feature, optimal dosing with TCAs is often more problematic than with SSRIs.

Traditionally, treatment with TCAs is begun at what is usually a subtherapeutic dose and gradually titrated upward to an effective antidepressant dose. This approach is taken so that the patient can develop some tolerance to the adverse effects caused by these drugs due to their ability to block specific neuroreceptors as discussed earlier in this section. In contrast, SSRIs as a class can usually be started at the effective dose from the beginning. As discussed in the next section, there is generally no need to titrate the dose of the SSRIs upward in most patients.

With TCAs, the physician can use therapeutic drug monitoring (TDM) to ensure that the patient is achieving plasma drug concentration within a range associated with the optimal antidepressant response with the minimum risk of adverse effects in most patients.²²¹ This is an advantage from a clinical pharmacology perspective, but is often viewed as a cumbersome disadvantage from a clinical practice standpoint. As discussed in the next section, TDM can also be used with SSRIs for the same purpose, although it is rarely done.

The difference between TCAs and SSRIs with regard to TDM is that it is a standard of care issue with TCAs, but not with SSRIs, due to the difference in their therapeutic indexes (ie, the difference between a dose that is therapeutic and one that is toxic). Patients who are slow metabolizers of TCAs can develop potentially toxic concentrations on conventional antidepressant doses of these medications because of the multiple SOAs affected by TCAs over their clinically relevant pha rmacological range. If the patient slowly clears these drugs either due to a genetically- or environmentally-induced deficiency in the cytochrome P450 enzymes responsible for their biotransformation and eventual elimination, they can develop concentrations that affect fast sodium channels and, hence, delay intracardiac conduction. Sufficient slowing can lead to conduction delays and set the stage for potentially life-threatening cardiac arrhythmias even though the patient is taking what is normally a therapeutic dose. The avoidance of potentially toxic concentrations is the primary reason for using TDM with TCAs.²²¹