Safety

• Therapeutic index
• Drug-drug interactions
  
  – Pharmacodynamics
  –Pharmacokinetics
  

Tolerability

Efficacy

• Overall
• Unique spectrum of activity
• Rate of response
• Maintenance and prophylaxis

Payment

Simplicity

• Ease of administration
  

Safety
• Therapeutic index: narrow. Serious toxicity can result from overdose, either acute ingestion or from gradual accumulation due to slow clearance
• Drug-drug interactions:
– Pharmacodynamic: prone to cause multiple types of such interactions due to their multiple mechanisms of action (Table 6.3)
– Pharmacokinetic: can be the target of such interactions but are not prone to cause them. Due to narrow therapeutic index, care should be taken when prescribing TCAs to patients on drugs known to inhibit CYP enzymes (Table 6.10)
Tolerability
• Poor due to numerous types of adverse effects mediated by the blockade of histamine receptors (eg, sedation), muscarinic acetylcholine receptors (eg, constipation), and alpha-1–adrenergic receptors (eg, orthostatic hypotension) (Tables 6.2, 6.3, and 6.7)
Efficacy
• Overall: highest response rates of any antidepressants. Clomipramine in particular has been found to be superior to two SSRIs, citalopram and paroxetine, in hospitalized patients with clinical depression
• Unique spectrum of activity: imipramine has been found effective in patients who have not benefited from treatment with the SSRI, sertraline
• Rate of response: 2 to 4 weeks
• Maintenance of response: established by controlled studies Payment
• Generic versions are available making these antidepressants the least expensive in terms of acquisition costs. These savings are likely offset by expenses arising from problems with their safety and tolerability (Table 7.10)
Simplicity
• Must titrate dose due to tolerability problems. Therapeutic drug monitoring should be done once early in treatment to guide dose adjustment. Therapeutic ranges have been established for most of these TCAs. Can be given once a day

Safety
• Therapeutic index: narrow. The only NSRIs available at present in the United States are secondary amine TCAs which have the same toxicity problems as tertiary amine TCAs (eg, amitriptyline). However, this safety problem is due to inhibition of fast sodium channels as opposed to norepinephrine reuptake inhibition. In fact, there are investigational, nontricyclic NSRIs (eg, reboxetine) which do not have a narrow therapeutic index in terms of cardiotoxicity
• Drug-drug interactions:
– Pharmacodynamic: limited at therapeutic concentrations to those produced by norepinephrine potentiation
– Pharmacokinetic: can be target of such interactions but not prone to cause them. Due to narrow therapeutic index, care should be taken when prescribing with drugs known to inhibit CYP enzymes (Table 6.10)
Tolerability
• Generally good. Adverse effects mediated by norepinephrine potentiation (Tables 6.2, 6.3, and 6.6)
Efficacy
• Overall: comparable to tertiary amine TCAs
• Unique spectrum of activity: have been found in several studies to be effective in approximately 50% of patients who have not benefited from treatment with a variety of SSRIs • Rate of response: 2 to 4 weeks
• Maintenance of response: established by controlled studies Payment
• Generic versions are available but cost almost as much as newer antidepressants (Table 7.10)
Simplicity
• Can start on an effective dose immediately. Therapeutic drug monitoring should be done once early in treatment to guide dose adjustment. Therapeutic ranges have been established for most of these TCAs. Can be given once a day

Safety
• Therapeutic index: wide. No serious systemic toxicity demonstrated, even after substantial overdose
• Drug-drug interactions:
– Pharmacodynamic: serotonin syndrome may occur when used with other serotonin agonists. Can potentiate dopamine antagonists in terms of extrapyramidal effects (eg, motor restlessness)
– Pharmacokinetic: considerable differences exist among SSRIs in terms of their potential for decreasing the rate of oxidative metabolism of a variety of drugs by inhibiting CYP enzymes: fluoxetine, fluvoxamine > paroxetine > citalopram, sertraline (Table 6.10). No known clinically significant effect of other drugs on the clearance of SSRIs
Tolerability
• Good. Nausea and loose stools can occur early and are dose dependent but tolerance typically develops. Sexual dysfunction (eg, anorgasmia) can occur in approximately 30% of patients (Tables 6.2, 6.3, and 6.6) Efficacy
• Overall: equivalent to TCAs in outpatients
• Unique spectrum of activity: can work in TCAs nonresponders • Rate of response: 2 to 4 weeks
• Maintenance of response: evidence from controlled studies Payment
• Brand name only available; see discussion (Table 7.10)
Simplicity
• Ease of administration: fluoxetine, paroxetine, and sertraline can be started at an effective dose immediately. Nonlinear pharmacokinetics of paroxetine likely contribute to an increased risk of experiencing an SRI discontinuation syndrome after abrupt cessation. The long half-life of fluoxetine and active metabolite, norfluoxetine, means time to maximum effect and time to washout can take up to 2 months

Safety
• Therapeutic index: wide. No serious systemic toxicity demonstrated. Dose-dependent hypertension going from 1% above placebo at doses £ 100 mg/day to 11% above placebo at doses ³ 300 mg/day. That fact is consistent with NE uptake inhibition occurring at higher doses
• Drug-drug interaction:
– Pharmacodynamic: same as SSRIs at low doses. NE-mediated interactions possible at higher doses
– Pharmacokinetic: has profile comparable to citalopram and sertraline in terms of no to minimal effects on most CYP enzymes (Table 6.10)
Tolerability
• Comparable to SSRIs at low dose; NE-mediated adverse effects at higher doses (Tables 6.2, 6.3, and 6.7)
Efficacy
• Overall: equivalent to TCAs. High-dose venlafaxine was superior to fluoxetine in double-blind study
• Unique spectrum of activity: possible efficacy in cases not responsive to TCAs or SSRIs
• Rate of response is a function of dose: 2 to 4 weeks at doses £ 150 mg/day and 4 to 7 days at doses of ³ 300 mg/day
• Maintenance of response: evidence from controlled studies
Payment
• Brand name only available; see discussion (Table 7.10)
Simplicity
• Ease of administration: can be started at an effective dosage (75 mg/day); once daily dosing with sustained-release formulation. Dose titration is not necessary for many patients but increasing the dose is a reasonable strategy if starting dose is ineffective

Safety
• Therapeutic index: wide. No serious systemic toxicity due to acute overdose
• Drug-drug interactions:
– Pharmacodynamic: can interact with other agents that decrease arousal or impair cognitive performance. Can interact with adrenergic agents affecting blood pressure regulation. Complex interactions with other serotonin-active agents
– Pharmacokinetic: substantially inhibits CYP 3A which is responsible for 50% of known oxidative drug metabolism, including its own metabolism (ie, nonlinear pharmacokinetics or autoinhibition)
Tolerability
• Dizziness, drowsiness, and confusion are dose-dependent adverse effects; hence the need for dose titration (Tables 6.2, 6.3, and 6.7)
Efficacy
• Overall: equivalent to TCAs in outpatients
• Unique spectrum of activity: none demonstrated
• Rate of response: 2 to 4 weeks
• Maintenance of response: evidence from controlled studies Payment
• Generic version of trazodone available. Brand name only for nefazodone. The latter has clinically important pharmacologic advantages over the former (Table 7.10)
Simplicity
• Ease of administration: requires dose titration and divided daily dosing for optimal antidepressant effect
Safety
• Therapeutic index: wide. No serious systemic toxicity due to acute overdose
• Drug-drug interactions:
– Pharmacodynamic: can interact with other agents that decrease arousal or impair cognitive performance. Can interact with adrenergic agents affecting blood pressure regulation. Complex interactions with other serotonin-active agents
– Pharmacokinetic: substantially inhibits CYP 3A which is responsible for 50% of known oxidative drug metabolism, including its own metabolism (ie, nonlinear pharmacokinetics or autoinhibition)
Tolerability
• Dizziness, drowsiness, and confusion are dose-dependent adverse effects; hence the need for dose titration (Tables 6.2, 6.3, and 6.7)
Efficacy
• Overall: equivalent to TCAs in outpatients
• Unique spectrum of activity: none demonstrated
• Rate of response: 2 to 4 weeks
• Maintenance of response: evidence from controlled studies Payment
• Generic version of trazodone available. Brand name only for nefazodone. The latter has clinically important pharmacologic advantages over the former (Table 7.10)
Simplicity
• Ease of administration: requires dose titration and divided daily dosing for optimal antidepressant effect

Safety
• Therapeutic index: wide in terms of acute drug overdose. There were three cases of agranulocytosis out of approximately 3000 patients in clinical trial program. That number was too small to establish with confidence the actual incidence or even whether there was a causal relation. Postmarketing experience has not indicated that toxicity is a major concern. Nevertheless, a white count should be obtained if a patient presents with signs of fever or infection
• Drug-drug interaction:
– Pharmacodynamic: can cause multiple types of such interactions due to multiple mechanisms of action (Table 6.3)
– Pharmacokinetic: unlikely to either be a victim or a cause of such interactions based on in vitro studies, but that should be confirmed by in vivo studies
Tolerability
• Primary problems are sedation due to histamine receptor blockade and weight gain due to 5-HT2C receptor blockade. These can be treatment limiting (Tables 6.2, 6.3, and 6.7). Dose titration may not help
Efficacy
• Overall: good; was superior to fluoxetine in double-blind study of hospitalized patients
• Unique spectrum of activity: worked in 54% of patients who had not benefited from treatment with amitriptyline. Open label studies have reported effectiveness in patients who had not benefited from SSRIs
• Rate of response: 2 to 4 weeks
• Maintenance of response: data limited to noncontrolled open label extension studies
Payment
• Brand name only available; see discussion (Table 7.10)
Simplicity
• Can start on an effective dose immediately. Sedation can be a problem, but starting with a lower dose may only decrease efficacy without improving tolerability, because mirtazapine is a more potent histamine receptor blocker than it is a serotonin and adrenergic receptor blocker. No rigorous data on whether higher doses increase either efficacy or tolerability

Safety
• Therapeutic index: narrow. The dose needed for efficacy (300-450 mg/day) is only 2 to 3 times less than the dose that causes seizures in 2% of patients. That is the reason the maximum recommended daily dose is 450 mg/day. Seizures can also occur following an acute overdose but are generally managed easily in a medical setting
• Drug-drug interaction:
– Pharmacodynamic: should potentiate and reduce the effects of other dopamine and norepinephrine agonists and antagonists, respectively
– Pharmacokinetic: can be affected by fluoxetine and probably others in a clinically significant way. Due to its narrow therapeutic index, care should be taken when prescribing bupropion to patients on drugs known to inhibit CYP enzymes. Case report data suggest that it can substantially inhibit CYP 2D6
Tolerability
• Good. Does not cause sexual dysfunction seen with antidepressants which are serotonin reuptake inhibitors (Tables 6.2, 6.3, and 6.7)
Efficacy
• Overall: probably less than TCAs • Unique spectrum of activity: can work in TCA nonresponders
• Rate of response: 2 to 4 weeks
• Maintenance of response: not demonstrated in formal studies
Payment
• Brand name only available; see discussion (Table 7.10)
Simplicity
• Ease of administration: requires divided daily dosing for antidepressant effect and dose titration to achieve efficacy and minimize seizure risk

Safety
• Therapeutic index: narrow. Serious toxicity can result from acute overdose
• Drug-drug interaction:
– Pharmacodynamic: hypertensive crisis can result from coadministration with tyramine and sympathomimetic agents. Serotonin syndrome can result from coadministration with serotonin agonists (eg, serotonin uptake inhibitors) (Table 6.2)
– Pharmacokinetic: inhibits the oxidative enzyme, MAOI, but effects on CYP enzymes have not been studied. Not known to be affected by other drugs in a clinically significant way
Tolerability
• Generally good, especially if kept to effective minimum dose. Ironically, main tolerability problem is hypotension (Table 6.3)
Efficacy
• Overall: Probably less than TCAs
• Unique spectrum of activity: can work in TCA nonresponders
• Rate of response: 2 to 4 weeks
• Maintenance of response: not adequately tested
Payment
• Generic versions are available making these antidepressants the least expensive in terms of acquisition costs (Table 7.10). These savings are likely offset by expenses arising from problems with their safety and tolerability
Simplicity
• Ease of administration: typically administered in divided daily doses. Dose titration recommended to optimize efficacy and minimize hypotension

• Starting dose may be given either as a once-a-day dose or on a divided schedule. Once an effective and tolerated dose has been established, it may be given on a once-a-day basis, but a divided dose may still be more prudent with a higher total dose and in patients who are elderly or debilitated. The maximum once-a-day dose of doxepin is 150 mg.
• Usual dose may be given either as a once-a-day dose or on a divided schedule.
• Therapeutic drug monitoring has been either demonstrated to increase the safe and efficacious use of this drug or theoretically should; demonstrated for amitriptyline, clomipramine, desipramine, imipramine, and nortriptyline. Theoretical for the rest, but has not been adequately studied.
• Doses should exceed 400 mg/day only in hospitalized patients who do not have a history of seizures and who have not benefited from an adequate trial of 400 mg/day.
• Not formally labeled by the FDA for the treatment of clinical depression but rather for obsessive-compulsive disorder; labeled for use as an antidepressant in other countries.
• Maximum daily dose should not be exceeded due to an increased risk of seizures.
• Dose should be given on a divided schedule (bid or tid).
• For some patients, it may be desirable to start at half the dose for 4 to 7 days to improve tolerance, particularly in terms of nausea.
• It is particularly important to administer in a manner most likely to minimize the risk of seizures. Dose increases should not exceed 100 mg/day in a 3-day period. Cautious dose titration can also minimize agitation, motor restlessness, and insomnia. Time between doses should be at least 4 hours for 100 mg IR doses, 6 hours for 150 mg IR doses, and 8 hours for SR doses. Increases above 300 mg/day should only be done in patients with no clinical effects after several weeks of treatment at 300 mg/day. Bupropion should be discontinued in patients who do not experience an adequate response after an adequate period on maximum recommended daily dose. Dosing in the elderly, the debilitated, and patients with hepatic and/or renal impairment has not been adequately studied so increased caution may be prudent.

Additional comments on dose titration: The package inserts for the following drugs indicate that they can be started at a dose which is usually effective to treat clinical depression: fluoxetine, mirtazapine, paroxetine, tranylcypromine, sertraline, venlafaxine. The following comments apply about the use of higher doses with these antidepressants. For fluoxetine, paroxetine, and sertraline: although fixed-dose studies in patients with clinical depression found no advantage on average to higher doses, an increase may be considered after several weeks on the starting dose if no clinical improvement has been observed. For mirtazapine, dose escalation should not be made at intervals of less than 1 to 2 weeks to adequately evaluate therapeutic response to a given dose. For tranylcypromine, improvement can be seen between 48 hours and 2 weeks of starting therapy; if not, dose increases in 10 mg/day increments may be made at intervals of 1 to 3 weeks.

The package inserts for the following drugs recommend starting at a lower than usually effective dose and titrate up to a dose which is usually effective to treat clinical depression in order to minimize tolerability or safety problems: amitriptyline, amoxapine, bupropion, citalopram, clomipramine, fluvoxamine, doxepin, imipramine, nefazodone, phenelzine, trazodone, and trimipramine. The following are additional comments about dose titration with these antidepressants: For the tricyclic antidepressants, the dose should be gradually increased during the first 2 weeks based on therapeutic drug monitoring and clinical assessment of efficacy and tolerability. For fluvoxamine, a lower than usually effective starting dose is recommended to improve tolerability. The dose should be increased every 4 to 7 days as tolerated until maximum therapeutic benefit is achieved. For citalopram, the starting dose is 20 mg/day with the recommendation to generally increase to 40 mg/day. While doses above 40 mg/day are not ordinarily recommended, some patients may require a dose of 60 mg/day. For nefazodone, a lower than usually effective starting dose is recommended to improve tolerability. Dose titration should occur in increments of 100 to 200 mg/day as determined by tolerability and the need for further clinical improvement. These incremental advances should be done using divided doses and at intervals of at least 1 week. It may be advisable to titrate up more slowly in elderly and debilitated patients. For phenelzine, a lower than usually effective starting dose is recommended to improve tolerability. Its dose should be increased to at least 60 mg/day at a fairly rapid pace consistent with good tolerability. For trazodone, the same comments apply as for nefazodone when trazodone is used as an antidepressant; however, it is now mainly used as a nonhabit-forming sedative given as a single bedtime dose of 50 to 200 mg as needed for sleep.