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The management of depression with pharmacologic agents and non-pharmacologic agents (ie, counseling and psychotherapy, electroconvulsant therapy, light therapy) may be warranted. (5, 6) Patients with depression have symptoms that generally reflect changes in the brain neurotransmitters serotonin, norepinephrine, and dopamine. The "dysregulation hypothesis" proposes that depression may be due to abnormalities in the pattern and responsiveness of neurotransmitter systems that result from modifications in the receptor sensitivity and function. Antidepressants are thought to increase levels of norepinephrine, serotonin, or dopamine at the synapse to restore equilibrium to neurotransmitter activity. This review will focus on antidepressant agents that are currently available on the University of Chicago Hospitals Formulary of Accepted Drugs and the newer agents which have become available in the past few years.
|Anti-inflammatory and analgesic||
Gram-negative antibiotics (some)
|Cardiovascular and antihypertensive||
Congestive heart failure
Systemic lupus erythematosus
Amyotrophic lateral sclerosis
Chronic pain syndrome
Mechanisms of Action
Antidepressants are classified by their chemical structure and mechanism of action. (table 4) Antidepressants are thought to increase levels of norepinephrine, serotonin, or dopamine at the synapse to restore equilibrium to neurotransmitter activity. Individual classes of antidepressants are distinguished by their side-effect profiles.
|Class||Mechanism of action|
|Serotonin/norepinephrine reuptake inhibitor|
|Monoamine oxidase inhibitor (phenelzine)||Monoamine oxidase inhibitor|
|SSRI (fluoxetine, sertraline, paroxetine)||Selective serotonin reuptake inhibitor|
|Aminoketone (bupropion)||Norepinephrine/dopamine reuptake inhibitor|
|Triazolopyridine (trazodone and nefazodone)||Serotonin reuptake inhibitor/serotonin antagonist|
|Tetracyclic (mirtazapine)||Presynaptic alpha-2 adrenergic/serotonin antagonist|
Nefazodone is an analog of trazodone which has actions on serotonergic neurons by potently antagonizing the 5-HT2 receptor in addition to inhibiting neuronal uptake of serotonin. (1, 5) Nefazodone also inhibits the reuptake of norepinephrine and acts as an antagonist at alpha-adrenergic receptors.
Amitriptyline, imipramine, nortriptyline, desipramine, phenelzine, fluoxetine, sertraline, paroxetine, trazodone, nefazodone, buproprion, venlafaxine, and mirtazapine are all approved by the Food and Drug Administration (FDA) for the treatment of depression. (13-25) The manufacturers of the TCAs indicate that endogenous depression is more likely to be alleviated by TCAs than other depressive states. Phenelzine is more likely to be effective in patients who are clinically characterized as "atypical", "nonendogenous", or "neurotic". These patients often have mixed anxiety and depression and phobic or hypochondriacal features. There is less conclusive evidence of phenelzine's usefulness with severely depressed patients with endogenous features. Phenelzine should rarely be the first antidepressant used. Rather, it is more suitable for use with those patients who have failed to respond to the drugs more commonly used for these conditions.
Many medications are available for the treatment of major depression. (26) Antidepressants are effective treatment for 65-75% of all patients with depression. All antidepressants, when given in comparable doses, are equally efficacious. The initial choice of an antidepressant is empiric and is typically based on the patient's prior history of response, family history of response, concomitant disease states,
profiles, potential for
with other medications, and
An adequate therapeutic trial for an antidepressant is generally giving the agent at adequate doses continuously for 4-6 weeks. Because of their more tolerable adverse effects and relative safety in overdose, newer antidepressants such as the SSRIs have largely replaced older TCAs and MAOIs as first-line drugs. However, TCAs and MAOIs remain valuable alternatives for patients with moderate to severe depression. Newer agents such as venlafaxine and nefazodone appear to be as effective as SSRIs in the treatment of depression. Bupropion may also be helpful in some patients. Trazodone is generally a less effective antidepressant and is frequently used as a second drug for SSRI-associated sleep disturbances.
One of the most common misdiagnoses of treatment-resistant depression occurs in medically ill patients who have not been given adequate doses of medication. (4) SSRIs may be less effective for more severe depression than TCAs and MAOIs. The fact that it is important that TCA
are in the therapeutic range for the attainment of an effective antidepressant response has been addressed frequently in the literature. (6) Increasing TCA
above the recommended ranges should be considered if there is an incomplete response to a 6-week trial of a TCA at the high end of the recommended range or at least two sequential plasma levels (drawn 10-14 hours after the last oral dose) have documented subtherapeutic values and the patient is considered to be compliant. Up to 50% of patients resistant to prior, adequate antidepressant trials may go on to have a good response to an MAOI. There is little data indicating benefit to be expected from increasing the dose of a SSRI. Venlafaxine may offer an alternative for treatment-resistant patients who have failed other classes of antidepressants, based on its pharmacology and efficacy. Combinations of a TCA with an SSRI or a TCA with an MAOI have also been documented in overall safety and efficacy in the literature.
|Condition||First choices||Second-line options||Alternatives|
TCAs (secondary amines or low-dose tertiary amines)|
T4 or T3
Secondary amine TCAs|
|Tertiary amine TCAs||ECT|
(always reduce dose)
|Sertraline||New antidepressants Secondary amine TCAs||Tertiary amine TCAs|
|Hyperthyroidism||Antidepressant and antihyperthyroid medications||Antidepressants from different groups||
|Hypothyroidism||T4 or T3||T4 or T3 + antidepressant (SSRIs, TCAs, new antidepressants)||
Secondary amine TCAs
Tertiary amine TCAs (for pain)|
Secondary amine TCAs
T4 or T3
Lithium (if on dialysis or closely monitored)
(closely monitor; see cardiovascular, renal, hepatic, pulmonary)
Secondary amine TCAs
Washout periods are recommended when switching from some antidepressants to others. (table 6)
|Drug switching FROM||MAOI||Fluoxetine||Other SSRI||Venlafaxine|
|Drug switching TO||Washout period|
|Venlafaxine||14 d***||5 w*||14 d*||
|Elective surgery**||10 d||
|*||Initial dosage should be low and increases should be gradual and cautiously prescribed.|
|**||General anesthesia, cocaine, and local anesthesia (eg, sympathomimetic vasoconstrictors).|
|***||Initial dosage should be low and increases should be gradual and cautiously prescribed. A recent case report of serotonin syndrome following previous treatment with phenelzine has been reported in association with venlafaxine therapy. This is a potentially fatal drug interaction which may occur even after discontinuing an MAOI for the recommended two weeks and then initiating an indirect acting amine or serotonergic agent.|
All antidepressants are contraindicated in patients with a history of hypersensitivity to any component. (13-26)
TCAs are contraindicated during the acute recovery period after a myocardial infarction.
Aged and cured meats|
Broad bean pods
MAOIs are contraindicated in patients with pheochromocytoma, congestive heart failure, a history of liver disease, or abnormal liver function. The potentiation of sympathomimetic substances and related compounds by MAOIs may result in hypertensive crisis.
MAOIs should not be used in combination with dextromethorphan or with CNS depressants (eg, alcohol, certain narcotics such as meperidine). Close monitoring is recommended when prescribing MAOIs with serotonergic drugs (eg, TCAs, SSRIs, trazodone, nefazodone, venlafaxine, narcotics) because serotonin levels may become dangerously elevated. This may precipitate serotonin syndrome, characterized by tachycardia, hyperactivity, hypertension, hyperpyretic crisis, and severe seizures. MAOIs should not be given with bupropion or buspirone. Patients on MAOIs should not undergo elective surgery requiring general anesthesia and should not be given cocaine or local anesthesia containing sympathomimetic vasoconstrictors. MAOIs are contraindicated in patients receiving guanethidine. These potential adverse effects can be fatal.
Side effects of TCAs include urinary retention, dry mouth, constipation, blurred vision, sedation, weight gain, and sexual dysfunction. (1, 5, 26) These effects frequently prevent patients from completing a full course of TCA therapy or from receiving full therapeutic dosages. Tolerance develops with some side effects (eg, sedation, dizziness) and the severity of some side effects decreases with time (eg, blurred vision). The secondary amines (eg, nortriptyline, desipramine) are better tolerated than the tertiary amines (eg, amitriptyline, imipramine) due to a lower binding affinity for muscarinic, histaminergic, and adrenergic receptors. Additionally, there have been reports of sudden death with desipramine in pediatric patients.
Nefazodone is associated with a lower frequency of sedation, orthostasis and priapism than trazodone. (1, 5, 26) Other side effects are fatigue, confusion, dizziness, asthenia, dry mouth, nausea, constipation, headache, and amblyopia.
Seizures are an uncommon (0.1-4% incidence) but serious adverse reaction associated with the use of antidepressant drugs. (28-41) Rosenstein and colleagues conducted a review of case reports, series of cases, and information from clinical trials of antidepressants to determine antidepressant-related seizure risk. These authors concluded that a significant proportion of antidepressant-related seizures occur in individuals with an identifiable predisposition. Caution should be used in prescribing antidepressant drugs to patients with a history of seizures or other predisposing conditions. There is also a
relationship between antidepressant drugs and seizures. Seizure incidence increases with high doses and is especially increased following overdose. Fluoxetine, sertraline, trazodone, and MAOIs appear to have a lower incidence of seizures than other antidepressant agents. The TCAs and bupropion appear to have an intermediate risk for seizures. The seizure rate for bupropion at recommended doses is similar to TCA rates.
|Class||Antidepressant||Sedation||Anticholinergic effects||Orthostatic hypotension||Weight gain|
Depression is associated with a significant risk of suicide. (42) TCAs and MAOIs have a low therapeutic index. (5, 26, 42) Suicidal patients can receive toxic or lethal doses either intentionally or accidentally with one week's worth of drug. Doses of 1500 mg of amitriptyline or imipramine in an adult or 8 mg/kg in a child can result in severe cardiotoxicity or death. Overdosage of TCAs can cause hypotension,
cardiac arrhythmias, coma and death. Toxicity is more likely if TCA plasma concentrations are > 1, 000 ug/L, however, cardiovascular toxicity (eg, QRS duration > 100 msec) may also be seen at lower TCA concentrations. Power and colleagues indicated that no clinical feature, electrocardiographic finding or plasma concentration in isolation was predictive of life-threatening TCA toxicity in the overdose patient who was maintaining an airway, not having seizures, and not experiencing malignant or premalignant arrhythmia. (42) SSRIs have a wide therapeutic index and are significantly safer when taken in overdose. Bupropion and venlafaxine have not at this time been associated with lethality in overdose. (27)
Excretion in Breast Milk
The efficacy of antidepressant drugs in the treatment of serious postpartum depression should be weighed against possible risks for the infant. Infant exposure can be minimized by using a secondary amine TCA (eg, nortriptyline) and by giving the drug as a single dose at bedtime while foregoing the night time feed. Close monitoring of a breast-fed infant is warranted. Imipramine and amitriptyline and their active metabolites have been found in the milk of lactating mothers in several studies. (44) Because no adverse reactions have been noticed in the babies, it is probably safe for mothers to breast feed while receiving imipramine and amitriptyline. Fluoxetine has been inadequately studied to date, but the long elimination half-life of the parent drug and its metabolite may make it possible that mothers receiving this drug will not be able to breast feed safely.
Current recommendations are to avoid the use of antidepressants during the first trimester if at all possible. Because of the greater experience with TCAs, Elia et al recommended them during gestation over other antidepressants. (43) Fluoxetine and buproprion are classified in FDA pregnancy category B; desipramine, phenelzine, sertraline, paroxetine, trazodone, nefazodone, venlafaxine, and mirtazapine in FDA pregnancy category C; and amitriptyline, imipramine, and nortriptyline in FDA pregnancy category D. (13-25)
The FDA pregnancy categories are defined as follows:
|A||Controlled studies in women have failed to demonstrate a risk to the fetus in the first trimester, and there is no evidence of a risk in later trimesters. The possibility of fetal harm appears remote.|
|B||Either animal-reproduction studies have not demonstrated a fetal risk and there are no controlled studies in pregnant women; or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility), that effect was not confirmed in controlled studies in women in the first trimester, and there is no evidence of a risk in later trimesters.|
|C||Either studies in animals have revealed adverse (teratogenic, embryocidal, or other) effects on the fetus and there are no controlled studies in women; or neither studies in animals nor women are available. These drugs should given only if the potential benefits justify the potential risk to the fetus.|
|D||There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (eg, if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).|
|X||Studies in animals or women have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience, or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. These drugs are contraindicated in women who are or may become pregnant.|
Close monitoring is recommended when prescribing TCAs with MAOIs because serotonin levels may become dangerously elevated. This may precipitate serotonin syndrome, characterized by tachycardia, hyperactivity, hypertension, hyperpyretic crisis, and severe
The potential adverse effects can be fatal.
Hepatic enzyme inhibitors (eg, cimetidine, SSRIs) can increase concentrations of TCAs, and hepatic enzyme inducers (eg, barbiturates, alcohol, carbamazepine) can decrease levels of TCAs.
MAOI (1, 5, 26)
MAOIs should not be used in combination with dextromethorphan or with CNS depressants (eg, alcohol, certain narcotics such as meperidine). Close monitoring is recommended when prescribing MAOIs with serotonergic drugs (eg, TCAs, SSRIs, trazodone, nefazodone, venlafaxine, narcotics) because serotonin levels may become dangerously elevated. This may precipitate serotonin syndrome, characterized by tachycardia, hyperactivity, hypertension, hyperpyretic crisis, and severe
MAOIs should not be given with bupropion or buspirone. Patients on MAOIs should not undergo elective surgery requiring general anesthesia and should not be given cocaine or local anesthesia containing sympathomimetic vasoconstrictors. MAOIs are contraindicated in patients receiving guanethidine. These potential adverse effects can be fatal.
Close monitoring is recommended when prescribing TCAs with MAOIs because serotonin levels may become dangerously elevated. This may precipitate serotonin syndrome, characterized by tachycardia, hyperactivity, hypertension, hyperpyretic crisis, and severe seizures. The potential adverse effects can be fatal.
Hypertensive crisis culminating in a cerebrovascular accident and death may occur when MAOIs are taken with tyramine-containing foods or sympathomimetic amines. (5) Patients should be warned and advised to avoid or greatly limit their intake of cheese, wines, and other tyramine-containing foods. (table 7) Many patients can tolerate limited quantities of items that contain moderate levels of tyramine (eg, red or white wine, bottled or canned beer). Over-the-counter cold and weight-loss products should also be avoided.
The cytochrome P450 enzyme family plays a major role in oxidative drug metabolism. (45-48) Drugs may be substrates, inhibitors, and/or inducers of cytochrome P450 enzymes. The majority of drug interactions associated with SSRIs are due to inhibition of cytochrome P450 enzymes or elevation of serotonin levels. (5) Inhibition of cytochrome P450 2D6 results in increased plasma levels of concomitantly administered beta-blockers and TCAs. Drugs dependent on cytochrome P450 3A4 metabolism include astemizole, calcium channel blockers, carbamazepine, cisapride, cocaine, cyclosporine, dextromethorphan, terfenadine, and triazolobenzodiazepines (alprazolam, midazolam, triazolam).
|Inhibitor drug||Cytochrome P450 enzymes inhibited||Substrate drugs|
Antiarrhythmics (type 1C)|
Antiarrhythmics (type 1C)|
Antiarrhythmics (type 1C)|
Pharmacogenetics is the study of the genetic factors that lead to individual differences in the response to drug therapy. (49) Often, phenotypes that lead to pharmacogenetic differences are found clustered within particular ethnic groups. Interindividual variability in cytochrome P450 2D6 activity is quite large. (46, 47) The impact of polymorphism on P450 enzymes involved in antidepressant metabolism depends on the importance of the metabolic pathway. Generally, adverse effects are more likely in slow metabolizers because of drug accumulation, and serum concentrations may be subtherapeutic in extremely rapid metabolizers. One group of investigators suggest that 30% of Chinese patients are slow metabolizers and thus are at risk for toxicity from usual doses of TCAs.
Nefazodone may interact with highly plasma protein bound drugs. (20) Nefazodone is also a potent inhibitor of cytochrome P450 3A4 and may increase the toxicity of drugs which are metabolized via that pathway. Coadministration of nefazodone with terfenadine, astemizole or cisapride is contraindicated. Combination of nefazodone with an MAOI can lead to serotonin syndrome.
Concomitant use of venlafaxine and monamine oxidase inhibiting compounds is contraindicated. Hyperpyretic crises or severe convulsive seizures may occur in patients receiving such combinations. The potential adverse effects can be fatal.
Plasma protein binding (%)
|t-1/2||half-life of drug (*) or metabolite (**)|
|T-max||time to maximum concentration|
|V-d||volume of distribution|
Some clinicians recommend that the plasma concentrations of imipramine, desipramine, and nortriptyline be monitored to determine if patients are receiving therapeutic dosages and to verify compliance. (5, 9) The utility of plasma concentration monitoring for MAOIs and the newer antidepressant agents has yet to be demonstrated.
|Antidepressant||Plasma concentration (ng/mL)|
|*||parent drug + metabolite|
|**||parent drug + metabolite, well-established therapeutic range|
|***||well-established therapeutic range|
To minimize the severity of side effects, therapy with a TCA can be initiated with a low dosage administered at bedtime. (5, 26) The dosage should be titrated upward slowly until a therapeutic effect is achieved. Doses of > 200 mg/day are rarely necessary except in
patients, rapid metabolizers, or patients receiving concomitant inducers (eg, smokers). Abrupt discontinuation of TCA therapy can precipitate withdrawal symptoms that are suggestive of cholinergic rebound (eg, dizziness, nausea, diarrhea, malaise, anxiety, insomnia, restlessness). Patients requiring prolonged therapy or receiving doses exceeding 300 mg/day are at the highest risk for withdrawal. To minimize this, the dosage should be gradually reduced by 25-50 mg/day/week and patients should be forewarned about potential withdrawal effects.
The initial starting dose of nefazodone is 200 mg/day but doses of 300-600 mg/day may be required for efficacy. (1, 5) Nefazodone must be dosed twice daily, and higher doses are needed for efficacy.
|Class||Antidepressant||Usual starting dose (mg/day)||Usual maintenance dose (mg/day)|
|MAOI||Phenelzine||0.5 mg/kg||1 mg/kg|
The manufacturer does not recommend the use of amitriptyline in patients under 12 years of age. (13) In adolescent patients, the manufacturer recommends 10 mg three times daily and 20 mg at bedtime as an initial dosage. However, Kashani found that amitriptyline administered in doses of 1 mg/kg/day orally in 3 divided doses, increased after 3 days to 1.5 mg/kg/day for the remainder of the 4 week study, produced a favorable response in children 9-12 years of age. (51)
The initial starting dose of imipramine in children is 1.5 mg/kg/day given in 1-4 divided doses with a dosage increased to 1 mg/kg every 3-4 days. (52) The daily dose should not exceed 5 mg/kg/day and children receiving doses of 3.5 mg/kg/day or more should be closely monitored. The manufacturer recommends that adolescents should initially receive 30-40 mg/day. (19) Doses exceeding 100 mg/day are generally not necessary.
The usual daily therapeutic dose of nortriptyline in adolescents is 30-50 mg daily in a single or divided doses. (25)
The usual daily therapeutic dose of desipramine in adolescents is 25-100 mg daily. (15) In more severely ill patients, the dosage can be gradually increased to 150 mg daily. The maximum recommended dose is 150 mg daily in adolescent patients.
Although some studies have suggested that SSRIs may not be as effective as secondary amine TCAs in elderly patients with certain types of depression, most authors indicate that SSRIs should be considered first-line agents for older adults because they lack the significant anticholinergic, cardiovascular, and sedative effects of TCAs. (53)
Clearance of amitriptyline and imipramine is reduced and postural hypotension is a risk in the elderly. (54) Some reviewers recommend that imipramine be avoided and that lower doses of amitriptyline with plasma concentration monitoring be used in elderly patients.
Clearance of desipramine does not appear to be affected by age, although decreased renal function may lead to accumulation of the hydroxylated metabolite. (54) However, the clinical implication for therapeutic or toxic effects is not established.
Clearance of nortriptyline is decisively lower only in elderly patients with concurrent medical illness, and decreased renal function may lead to accumulation of the hydroxylated metabolite. (54) However, the clinical implication for therapeutic or toxic effects is not established.
Limited information is currently available on fluoxetine in elderly patients. (54) The initial starting dose is 10 mg daily and the usual daily therapeutic dose is 20-40 mg. (53)
The initial starting dose of paroxetine is 10 mg daily and the usual daily therapeutic dose is 20-40 mg. (53)
The initial starting dose of sertraline is 25-50 mg daily and the usual daily therapeutic dose is 100-150 mg. (53)
Elderly patients should begin nefazodone therapy with 50 mg twice daily, increasing as necessary up to 200 mg twice daily. (5, 20)
Dosage in Renal Dysfunction
There is no dosage adjustment necessary for TCAs in patients with renal dysfunction. Neither is there dosage adjustment in patients receiving hemodialysis or peritoneal dialysis due to the high plasma protein binding and large volume of distribution of TCAs.
There is no dosage adjustment necessary for phenelzine in patients with renal dysfunction. (14)
Initial dosing of paroxetine is recommended as 10 mg daily, titrated to a maximum of 40 mg daily. (16)
The pharmacokinetics and dosage of sertraline in patients with significant renal disease have not been determined. (21)
Dosage in Hepatic Dysfunction
It is recommended that TCAs be used in lower dosages in patients with hepatic dysfunction. (56)
Sertraline is extensively metabolized in the liver. (21) In patients with hepatic impairment or cirrhosis, a lower or less frequent dosage should be used.
The recommended initial dosing of paroxetine in patients with hepatic insufficiency is 10 mg daily, titrated to a maximum of 40 mg daily. (16)
Duration of Therapy
Antidepressant therapy may require 4-6 weeks before benefits are apparent. (5, 10, 57) An adequate trial should be given before upward dose titration. If a patient fails with one agent, a drug from another class may be effective. Treatment of acute depression should continue at the full dosage for approximately 4-9 months after the induction of remission. Continuation of therapy for less than 4 months significantly increases the risk of relapse. Prophylactic treatment reduces the risk of new episodes in those patients with recurrent episodes. Patients with recurrent depression who have suffered two episodes or more in 5 years may need long-term antidepressant treatment.
A recent analysis of pharmacoeconomic studies indicated that the newer antidepressants were the least expensive overall. (9) This was due to fewer hospitalizations, emergency room visits, and physician visits, which were more significant expenses than the cost of the drugs.
|Class||Antidepressant||Inpatient cost* ($/day)||Outpatient cost** ($/month)||Average wholesale price** (26) ($/month)|
|TCA||Amitriptyline||0.03-0.11||4.50||10 mg x 30||2.57||generic|
|16.30||50 mg x 90||74.48||Elavil(r)|
|Imipramine||0.08-3.34||13.50||50 mg x 90||3.70||generic|
|Nortriptyline||0.29-1.15||86.80||20 mg x 120||11.66||generic|
|Desipramine||0.22-0.72||73.80||50 mg x 120||24.53||generic|
|MAOI||Phenelzine||1.60||50.00||15 mg x 100||48.29||Nardil(r)|
|SSRI||Fluoxetine||2.01-4.02||79.30||20 mg x 30||72.51||Prozac(r)|
|Sertraline||1.72-2.58||70.80||50 mg x 30||66.54||Zoloft(r)|
|74.80||100 mg x 30|
|Paroxetine||1.65||76.00||20 mg x 30||61.95||Paxil(r)|
|Triazolopyridine||Trazodone||0.06-0.40||39.30||50 mg x 90||10.53||generic|
|Nefazodone||1.55-3.10||59.60||100 mg x 60||58.14||Serzone(r)|
|65.10||150 mg, 200 mg, 250 mg x 60|
|Aminoketone||Bupropion||1.85-3.04||65.00||75 mg x 90||74.66||Wellbutrin(r)|
|86.80||100 mg x 90|
|45.90||150 mg SR x 30|
|Phenylethylamine||Venlafaxine||1.84-4.59||39.70||37.5 mg x 30||68.68||Effexor(r)|
|39.10||75 mg x 30|
|73.20||75 mg x 60|
|45.50||100 mg x 30|
|Tetracyclic||Mirtazapine||1.65-4.95||73.00||15 mg x 30||61.20||Remeron(r)|
|*||based on University of Chicago Hospitals acquisition costs|
|**||based on UCH outpatient costs|
The selection of an antidepressant should be based on the individual patient's tolerability and compliance factors,
profiles, knowledge of drug
the presence of comorbid conditions, potential for
long-term tolerability, previous response to therapy, and
The TCAs and MAOIs were the only antidepressants available in the United States for decades. However, patients often had to endure difficult-to-tolerate or toxic side effects with these agents. Since the mid-1980s, newer agents have become available. Generally, all of these agents are considered to be equally effective for uncomplicated unipolar depression.
TCAs are no longer considered the antidepressants of choice for uncomplicated unipolar depression due to their unfavorable side effect profile and lethality when taken in overdose. However, the use of TCAs also extends to disorders other than depression (eg, enuresis, chronic pain, and migraine prophylaxis) due to their effects on cholinergic, histaminergic, noradrenergic, serotonergic, and dopaminergic receptors. MAOIs are generally reserved for second-line therapy of depression because of their side effects, low therapeutic index, and potential to cause life-threatening hypertensive reactions. However, patients with atypical depression or severe treatment-refractory depression may have a good response to MAOIs. MAOIs are an effective treatment of depression and have a role in the therapy of comorbid anxiety and depression, atypical depression, treatment-refractory depression, panic disorder, and bulimia.
Recently, the SSRIs have been found to have comparable efficacy and better-tolerated adverse effects than either the TCAs or the MAOIs. This has established the SSRIs as first-line agents for uncomplicated unipolar depression and dysthymia.
Of the newer agents, nefazodone and venlafaxine are alternative agents for the treatment of uncomplicated depression and treatment-resistant depression. Their cost is comparable to that of the SSRIs. Nefazodone appears to possess significantly fewer adverse reactions than trazodone. Bupropion is excellent second-line therapy for patients who have failed SSRI treatment. Bupropion may also be combined with SSRIs in the management of treatment-refractory depression. Mirtazapine does not appear to offer any advantages over the currently available antidepressants at this time.
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|13.||Amitriptyline hydrochloride Product Information. East Hanover: Sidmak Laboratories, Inc. May, 1995.|
|14.||Phenelzine sulfate (Nardil(r)) Product Information. Morris Planes: Parke-Davis. July, 1995.|
|15.||Desipramine hydrochloride Product Information. East Hanover: Sidmak Laboratories, Inc. April, 1995.|
|16.||Paroxetine hydrochloride (Paxil(r)) Product Information. Philadelphia: SmithKline Beecham Pharmaceutical. July, 1996.|
|17.||Fluoxetine hydrochloride (Prozac(r)) Product Information. Carolina: Eli Lilly Industries. March 25, 1996.|
|18.||Trazodone hydrochloride Product Information. Elizabeth: Purepac Pharmaceutical Co. July, 1995.|
|19.||Imipramine hydrochloride Product Information. Elmwood Park: Biocraft Laboratories, Inc. April, 1995.|
|20.||Nefazodone hydrochloride (Serzone(r)) Product Information. Princeton: Bristol-Myers Squibb Company. October, 1995.|
|21.||Sertraline hydrochloride (Zoloft(r)) Product Information. New York: Pfizer, Inc. November, 1996.|
|22.||Bupropion hydrochloride (Wellbutrin(r)) Product Information. Research Triangle Park: January, 1996.|
|23.||Venlafaxine hydrochloride (Effexor(r)) Product Information. Philadelphia: Wyeth-Ayerst Company. July 17, 1995.|
|24.||Mirtazapine (Remeron(r)) Product Information. West Orange: Organon. April, 1996.|
|25.||Nortriptyline hydrochloride Product Information. Danbury: Danbury Pharmacal, Inc. January, 1995.|
|26.||Anonymous. Drugs for psychiatric disorders. Medical Letter 1997; 39: 33-40.|
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Dr. Bob is Robert Hsiung, MD, firstname.lastname@example.org
Revised: November 19, 2001 ("tetracyclic")
Original copyright 1997 University of Chicago Hospitals.
Web page copyright 1997-2001 Robert Hsiung.