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Antidepressant Update

Lora Armstrong, R.Ph., B.C.P.S.
Department of Pharmaceutical Services, University of Chicago Hospitals
Topics in Drug Therapy, Volume 35, Number 6
June, 1997

Index

Introduction

Major depression has a lifetime prevalence rate of 17%. (1) Depression is more common in women and is seen throughout life. The American Psychiatric Association has published standardized criteria for diagnosing depressive disorders in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) in 1994. (2, 3) (table 1) A major depressive disorder may occur as either a single or recurrent event. The cause of depression is not clearly understood. It is important for the clinician to recognize whether or not physical illness or the medications or treatments used for treating physical illness are inducing the depression. (4) (table 2, table 3)

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.

Table 1. Criteria for major depressive episode (3, 7)
  1. Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.

    1. Depressed mood most of the day, nearly every day

    2. Marked diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day

    3. Significant weight loss (when not dieting) or weight gain, or decrease or increase in appetite nearly every day

    4. Insomnia or hypersomnia nearly every day

    5. Psychomotor agitation or retardation nearly every day (not merely subjective feelings of restlessness or being slowed down)

    6. Fatigue or loss of energy nearly every day

    7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or feelings of guilt about being sick)

    8. Diminished ability to think or concentrate, or indecisiveness, nearly every day

    9. Recurrent thoughts of death (not merely fear of dying), recurrent suicidal ideation, or a suicide attempt.

  2. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

  3. The symptoms are not due to the direct physiologic effects of a substance or a general medical condition.

  4. The symptoms do not meet criteria for a Mixed Episode and are not better accounted for by Bereavement.

Table 2. Medications that may precipitate depression (2, 7-10)
Class Medication
Anti-inflammatory and analgesic Indomethacin
Pentazocine
Phenacetin
Phenylbutazone
Antimicrobial Cycloserine
Ethambutol
Gram-negative antibiotics (some)
Sulfonamides
Cardiovascular and antihypertensive Clonidine
Digitalis
Diuretics
Guanethidine
Hydralazine
Indapamide
Methyldopa
Prazocin
Procainamide
Propranolol
Reserpine
CNS Alcohol
Amantadine
Amphetamines
Barbiturates
Benzodiazepines
Carbamazepine
Chloral hydrate
Cocaine
Haloperidol
L-dopa
Phenothiazines
Succinimides
Hormonal ACTH
Corticosteroids
Estrogen
Melatonin
Oral contraceptives
Progesterone
Miscellaneous Antineoplastic agents
Cimetidine
Disulfuram
Organic pesticides
Physistigmine

Table 3. Medical and psychiatric disorders associated with depression (4, 7, 9, 11)
Class Disorder
Cardiovascular disorders Cerebral arteriosclerosis
Chronic bronchitis
Congestive heart failure
Emphysema
Myocardial infarction
Paroxysmal dysrrhythmias
Pneumonia
Collagen disorders Rheumatoid arthritis
Systemic lupus erythematosus
Deficiency states Anemia
Pernicious anemia
Wernicke's encephalopathy
Endocrine disorders Acromegaly
Addison's disease
Cushing's disease
Diabetes mellitus
Hyperparathyroidism
Hyperthyroidism
Hypoparathyroidism
Hypothyroidism
Insulinoma
Pheochromocytoma
Pituitary dysfunction
Infectious disorders AIDS
Encephalitis
Fungal infections
Influenza
Meningitis
Mononucleosis
Neurosyphilis
Tuberculosis
Malignant disorders Breast
Gastrointestinal
Lung
Pancreas
Prostate
Metabolic disorders Electrolyte imbalance
Hepatic encephalopathy
Hypokalemia
Hyponatremia
Pick's disease
Uremia
Wilson's disease
Neurologic disorders Alzheimer's disease
Amyotrophic lateral sclerosis
Brain tumors
Chronic pain syndrome
Cruetzfeld-Jakob disease
Huntington's disease
Multiple sclerosis
Myasthenia gravis
Parkinson's disease
Stroke
Trauma (concussion)
Psychiatric disorders Alcoholism
Anxiety disorders
Eating disorders
Schizophrenia

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.

Table 4. Classification of antidepressants by primary mechanism of action (5, 12)
Class Mechanism of action
Tricyclic
Phenylethylamine (venlafaxine) 		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

Tricyclic

Tricyclic antidepressants (TCAs) act to inhibit norepinephrine and serotonin reuptake in the central nervous system. (1)

Monoamine oxidase inhibitor

Monoamine oxidase inhibitors (MAOIs) nonspecifically inhibit type A and type B monoamine oxidases to block the degradation of norepinephrine, serotonin, and dopamine. (1, 5) Monoamine oxidase is an intracellular enzyme located in the mitochondria that catalyzes the conversion of biogenic amines (ie, norepinephrine and serotonin) to their deaminated products. MAOIs inhibit monoamine oxidase, presumably resulting in an increase in the concentration of monoamines in the synapse. However, monoamine oxidase is also responsible for metabolizing compounds, such as tyramine, which are present in certain aged cheeses and other food substances.

Selective serotonin reuptake inhibitor

Selective serotonin reuptake inhibitors (SSRIs) bind to the serotonin transporter and inhibit reuptake, enhancing serotonin activity within the synapse. (1, 5) At clinical doses, the SSRIs have little effect on the norepinephrine or dopamine transporters and a low affinity for the histaminic, muscarinic/cholinergic, and alpha receptors.

Triazolopyridine

Trazodone is a 5-HT2 receptor antagonist that also inhibits serotonin reuptake. (1, 5) The inactive metabolite of trazodone (m-CPP) also possesses postsynaptic serotonin agonist activity.

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.

Aminoketone

Bupropion is thought to inhibit norepinephrine reuptake. (1, 5)

Phenylethylamine

Venlafaxine and its pharmacologically active metabolite (O-desmethylvenlafaxine) inhibit the reuptake of norepinephrine and serotonin with little effect on dopamine. (1, 5)

Tetracyclic

Mirtazapine is a selective presynaptic alpha-2-adrenergic receptor antagonist that enhances transmission of norepinephrine due to alpha-2-autoreceptor blockade and serotonin due to alpha-2-heteroreceptor blockade. (5)

Indications

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.

Efficacy

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, adverse-effect profiles, potential for drug interactions with other medications, and cost. 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.

Treatment-resistant depression

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 levels are in the therapeutic range for the attainment of an effective antidepressant response has been addressed frequently in the literature. (6) Increasing TCA dosages 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.

Table 5. Somatic treatments of depression in the patient with medical illness (4)
Condition First choices Second-line options Alternatives
Cardiovascular disorders SSRIs
Bupropion		 ECT
Psychostimulants
Beta-blockers
Buspirone		 ECT
TCAs
MAOIs
Mood stabilizers
Diabetes mellitus SSRIs
New antidepressants		 TCAs (secondary amines or low-dose tertiary amines)
MAOIs		 ECT
Buspirone
Psychostimulants
T4 or T3
Mood stabilizers
Gastrointestinal disorders Secondary amine TCAs
New antidepressants		 Tertiary amine TCAs ECT
Hepatic disorders
(always reduce dose)		 Sertraline New antidepressants Secondary amine TCAs Tertiary amine TCAs
HIV Bupropion
SSRIs
Psychostimulants		 TCAs ECT
Hyperthyroidism Antidepressant and antihyperthyroid medications Antidepressants from different groups
Hypothyroidism T4 or T3 T4 or T3 + antidepressant (SSRIs, TCAs, new antidepressants) ECT
Other antidepressants
Psychostimulants
Malignant disorders New antidepressants
Secondary amine TCAs
Psychostimulants		 Tertiary amine TCAs (for pain)
MAOIs		 ECT
Neurologic disorders New antidepressants
Secondary amine TCAs		 Selegiline
Anticonvulsants
T4 or T3		 Bromocriptine
Pulmonary disorders Activating antidepressants
Buspirone		 Sedating antidepressants
ECT
Renal disorders Fluoxetine
Sertraline		 TCAs
New antidepressants
Psychostimulants		 ECT
Anticonvulsants
Lithium (if on dialysis or closely monitored)
Transplantation
(closely monitor; see cardiovascular, renal, hepatic, pulmonary)		 New antidepressants
Secondary amine TCAs

Safety

Washout Periods

Washout periods are recommended when switching from some antidepressants to others. (table 6)

Table 6. Recommended washout periods (13-17, 19,21 , 23, 25)
Drug switching FROM MAOI Fluoxetine Other SSRI Venlafaxine
Drug switching TO Washout period
TCA 14 d*


MAOI
5 w
7 d
SSRI 14 d*


Bupropion 14 d


Venlafaxine 14 d*** 5 w* 14 d*
Buspirone 10 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.

Contraindications

All antidepressants are contraindicated in patients with a history of hypersensitivity to any component. (13-26)

TCA (13, 15, 19, 25)

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.

TCAs are contraindicated during the acute recovery period after a myocardial infarction.

MAOI (14)

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.

Table 7. Foods and medications restricted with MAOIs (5)
Foods Medications
Aged and cured meats
Aged cheeses
Anchovies
Banana peel
Broad bean pods
Chicken figs
Fish
Liver
Marmite
Pepperoni
Pickled herring
Poultry
Sauerkraut
Sausage
Soy sauce
Soybean condiments
Tap beer		 Amphetamines
Antidepressants, other
Appetite suppressants
Cocaine
Decongestants
Ephedrine
Sympathomimetics

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.

SSRI (16, 17, 21)

The SSRIs may interact with an MAOIs or other central serotonin agonists to result in serotonin syndrome. (5, 26, 45) The potential adverse effects can be serious or even fatal.

Triazolopyridine (20)

Combination of trazodone or nefazodone with an MAOI can lead to serotonin syndrome. Coadministration of nefazodone with terfenadine, astemizole or cisapride is contraindicated.

Aminoketone (22)

Bupropion is contraindicated in patients with a history of seizure disorder. Bupropion is also contraindicated in patients with a current or prior diagnosis of bulimia or anorexia nervosa because of a higher incidence of seizures in such patients. Bupropion should not be administered concomitantly with an MAOI.

Phenylethylamine (23)

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.

Adverse Effects

TCA

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.

MAOI

Adverse reactions associated with MAOIs are generally more frequent and severe than with other antidepressants. (1, 5, 26) However, they can be minimized by reducing the dosage and carefully monitoring the patient. The most common dose-related side effect is orthostatic hypotension. Other common side effects are sedation, palpitations, dizziness, insomnia, constipation, tachycardia, agitation, peripheral edema, sexual dysfunction, weight gain, myoclonic jerks, and muscle cramps.

SSRI

The SSRIs are generally better tolerated than the TCAs because of their low affinity for the histaminergic, cholinergic, and alpha-adrenergic receptors. (1, 5, 26) The most common adverse effects include nausea, headache, nervousness, incoordination, insomnia, fatigue, sexual dysfunction, and tremor. Nausea and headache usually resolve with continued treatment (within 1-2 weeks) or dosage reduction. Jitteriness and insomnia early in treatment can be minimized by initiating lower doses or adding a benzodiazepine. Paroxetine often has mild anticholinergic effects. Sexual dysfunction is manifested as ejaculatory delay and impotence in men and anorgasmia in women.

Triazolopyridine

Trazodone is associated with a high degree of sedation. (1, 5, 26) Other side effects include orthostatic hypotension, dizziness, headache, and nausea. Rare cases of priapism have also been reported.

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.

Aminoketone

Side effects of bupropion include tremors, agitation, headache, dizziness, vision disturbances, palpitations, insomnia, dry mouth, constipation, and nausea. (1, 5, 26) The most serious side effect is the propensity to induce seizures when the total daily dose exceeds 450 mg or when single doses exceed 150 mg.

Phenylethylamine

Most adverse effects associated with venlafaxine are mild to moderate, occur early in the course of treatment, and resolve with continued therapy. (1, 5, 26, 27) Nausea occurs most commonly and is dose-related. It can be minimized by starting therapy with lower dosages (25 mg) and titrating upward gradually. Nausea diminishes with time once the maintenance dose is reached. Sweating, tremor, and agitation occur only at higher doses. Significant dose-dependent increases in blood pressure have been reported at dosages greater than 75 mg/day and limit use in patients with borderline or existing hypertension. Other adverse effects include nervousness, dry mouth, constipation, fatigue, anorexia, somnolence, insomnia, dizziness, abnormal ejaculation, and headache.

Tetracyclic

Sedation is a prominent effect of mirtazapine. (5, 26) Weight gain, dizziness, dry mouth, increased appetite, and constipation have also been reported.

Seizure Potential

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 dose-dependent 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.

Table 8. Adverse effects associated with antidepressants (5, 10)
Class Antidepressant Sedation Anticholinergic effects Orthostatic hypotension Weight gain
TCA Amitriptyline +++ +++ +++ +++
Imipramine ++ ++ ++ +++
Nortriptyline ++ + + +
Desipramine + + + +
MAOI Phenelzine + 0 +++ +++
SSRI Fluoxetine + 0 0 -
Sertraline + 0 0 -
Paroxetine + 0/+ 0 +
Triazolopyridine Trazodone +++ 0 ++ ++
Nefazodone ++ 0 + +
Aminoketone Bupropion 0 0 0 0
Phenylethylamine Venlafaxine + 0 + 0
Tetracyclic Mirtazapine +++ 0/+ 0

Toxicology

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, seizures, 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.

Teratogenicity

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.

Drug Interactions

TCA (5)

Hepatic enzyme inhibitors (eg, cimetidine, SSRIs) can increase concentrations of TCAs, and hepatic enzyme inducers (eg, barbiturates, alcohol, carbamazepine) can decrease levels of TCAs.

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.

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 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.

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.

SSRI

The SSRIs may interact with an MAOIs or other central serotonin agonists to result in serotonin syndrome. (5, 26, 45) The potential adverse effects can be serious or even fatal.

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).

Table 9. Selected potential cytochrome P450 drug interactions (5, 48, 49)
Inhibitor drug Cytochrome P450 enzymes inhibited Substrate drugs
Fluoxetine 2C9 (moderate)
2C19 (minimal)
2D6 (expected)
3A4 (moderate)		 Antiarrhythmics (type 1C)
Antipsychotics
Carbamazepine
Cocaine
Phenytoin
TCAs
Sertraline 2C9 (expected)
2D6 (moderate-expected)
3A4 (moderate)		 Antiarrhythmics (type 1C)
Antipsychotics
Carbamazepine
Cocaine
Diazepam
TCAs
Tolbutamide
Paroxetine 2D6 (expected)
3A4 (minimal)		 Antiarrhythmics (type 1C)
Antipsychotics
TCAs
Nefazodone 3A4 (expected) Alprazolam
Astemizole
Cisapride
Clozapine
Cocaine
Haloperidol
Midazolam
Terfenadine
Triazolam

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.

Triazolopyridine

Trazodone has relatively few known drug-drug interactions. (1) Combination of trazodone with an MAOI can lead to serotonin syndrome.

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.

Aminoketone

Drug-drug interactions are not a significant problem with bupropion. (1) Bupropion should not be administered concomitantly with an MAOI.

Phenylethylamine

Venlafaxine is a very weak inhibitor of cytochrome 2D6. (5)

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.

Tetracyclic

Concomitant administration of mirtazapine and other central nervous system depressants (eg, benzodiazepines and alcohol) may result in increased impairment. (24)

Pharmacokinetics

Table 10. Comparative pharmacokinetics of antidepressants (7, 24, 49)
Class Antidepressant t-1/2* (h) T-max (h) F (%) V-d (L/kg) Plasma protein binding (%) Active metabolites t-1/2** (h)
TCA Amitriptyline 9-46 2-12 40-60 6.4-36 96 Nortiptyline 18-48
Imipramine 6-28 1-4 60-100 9-23 80-96 Desipramine 12-28
Nortriptyline 18-84 2-6 60-100 15-23 87-93 10-hydroxynortriptyline 18-48
Desipramine 11-46 3-6 33-51 ND 73-92 2-hydroxydesipramine ND
MAOI Phenelzine 1.5-4 ND ND ND ND ND ND
SSRI Fluoxetine 4-6 days 6-8 72-90 12-42 95 Norfluoxetine 4-16 days
Sertraline 26 4-9 80-95 20 95 Desmethylsertraline 2-4 days
Paroxetine 21 3-8 > 90 3-28 95 None NA
Triazolopyridine Trazodone 6-13 1-2 60-80 1-2 89-95 m-CPP > 4
Nefazodone 2-4 1-3 > 90 NA > 95 m-CPP
Hydroxynefazodone
Triazoledione		 > 4
> 4
> 4
Aminoketone Bupropion 10-21 1-3 > 80 27-63 80 Hydroxybupropion
Erythrobupropion
Theohydrobupropion		 22
27
20
Phenylethylamine Venlafaxine 4 1-6 > 90 5-19 27 O-desmethylvenlafaxine 10
Tetracyclic Mirtazapine 20-40 2 50 ND 85 Several ND

t-1/2half-life of drug (*) or metabolite (**)
T-maxtime to maximum concentration
Fbioavailability
V-dvolume of distribution
m-CCPm-chlorophenylpiperazine
NDno data
NAnot available

Plasma concentrations

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.

Table 11. Therapeutic plasma concentrations (1, 9)
Antidepressant Plasma concentration (ng/mL)
Amitriptyline 60-250*
Imipramine > 150-250**
Nortriptyline 50-150***
Desipramine > 125-300**
Trazodone 800-1600
Bupropion 50-100*

*parent drug + metabolite
**parent drug + metabolite, well-established therapeutic range
***well-established therapeutic range

Dosage

Adult Dosage

TCA

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 treatment-resistant 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.

MAOI

Therapy with an MAOI should be started with a low dosage and titrated over 2-4 weeks according to the patient's tolerance and response. (5, 26) To minimize insomnia, the dosage can be administered in the morning. When discontinued, the MAOI should be gradually tapered to avoid precipitating withdrawal symptoms of vivid nightmares, agitation, frank psychosis, and convulsions.

SSRI

SSRIs may be taken once a day. (5, 26) Abrupt discontinuation of an SSRI may result in withdrawal, characterized by vivid dreams, nightmares, tremor, dizziness, crying spells, nausea, disorientation, and poor concentration. To avoid withdrawal, the dosage of the SSRI should be gradually tapered down over 7-10 days. However, this may not be necessary with fluoxetine because of its extended half-life.

Triazolopyridine

Therapy with trazodone should begin with 50-100 mg at bedtime and be gradually increased, if needed, to 200-400 mg/day. (1, 5) Tolerance or dependence does not develop with trazodone.

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.

Aminoketone

Therapy with bupropion should begin with 75 mg twice daily and be gradually increased, if needed, to 300 mg/day in three divided doses. (5)

Phenylethylamine

The initial starting dose of venlafaxine is 75 mg administered in 2-3 divided doses per day. (5, 26, 50) The dosage should be titrated slowly (at 4-day intervals), depending on the therapeutic response, to a maximum of 375 mg/day. The drug should be taken with food and must be dosed in 2-3 divided doses per day. A withdrawal syndrome similar to SSRIs has been reported with venlafaxine. To avoid withdrawal, the dosage should be gradually tapered down over 7-10 days.

Tetracyclic

Therapy with mirtazapine should be initiated at 15 mg daily administered prior to sleep in the evening. (24)

Table 12. Usual adult dosages (5)
Class Antidepressant Usual starting dose (mg/day) Usual maintenance dose (mg/day)
TCA Amitriptyline 75 75-300
Imipramine 75 75-300
Nortriptyline 10-50 50-200
Desipramine 75 75-300
MAOI Phenelzine 0.5 mg/kg 1 mg/kg
SSRI Fluoxetine 20 20-40
Sertraline 50 100-150
Paroxetine 20 20
Triazolopyridine Trazodone 50 50-400
Nefazodone 200 300-600
Aminoketone Bupropion 200 300-450
Phenylethylamine Venlafaxine 75 150-375
Tetracyclic Mirtazapine 15 15-45

Pediatric Dosage

TCA

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.

MAOI

The manufacturer does not recommend phenelzine for children under the age of 16. (14) There are no controlled studies for safety in this age group.

Geriatric Dosage

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)

TCA

Elderly patients are more sensitive to the anticholinergic effects of TCAs and may develop confusion or delirium even at moderate doses or with concurrent use of other anticholinergic drugs. (26) Orthostatic hypotension in the elderly can lead to falls and is least likely to occur with nortriptyline. Large interindividual pharmacokinetic variations appear to occur. (54) Altered drug metabolism has major implications. In elderly patients, TCAs increase the risk of falls and fractures. (5) In patients with heart disease, TCAs lower the threshold for bundle branch block, complete heart block, and sudden death.

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.

SSRI

The elderly generally require smaller doses but show a similar time course of response to antidepressant therapy with SSRIs. (53)

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)

Triazolopyridine

Clearance of trazodone is diminished somewhat in elderly patients. (54) The need for a reduced dosage can be anticipated, although a relationship between plasma concentration and clinical effect is not established.

Elderly patients should begin nefazodone therapy with 50 mg twice daily, increasing as necessary up to 200 mg twice daily. (5, 20)

Tetracyclic

Oral clearance of mirtazapine is reduced in elderly individuals. (24) No unusual adverse age-related phenomena were identified in this group; however, caution is indicated with elderly patients.

Dosage in Renal Dysfunction

TCA

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.

MAOI

There is no dosage adjustment necessary for phenelzine in patients with renal dysfunction. (14)

SSRI

A lower or less frequent dosage of fluoxetine is recommended in patients with severe renal insufficiency due to the possibility of increased sensitivity to the drug or its metabolites due to accumulation. (17) The large volume of distribution and high plasma protein binding would suggest that fluoxetine is not removed by hemodialysis or peritoneal dialysis.

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)

Triazolopyridine

Dosage adjustments of neither trazodone nor nefazodone are required in renal insufficiency. (55)

Aminoketone

Bupropion and its metabolites are almost completely excreted through the kidney. (22) The manufacturer indicates that patients with renal failure should receive a reduced dosage of bupropion initially and be closely monitored for toxic events.

Phenylethylamine

The dosage of venlafaxine should be reduced by 25-50% depending on the degree of renal impairment. If the glomerular filtration rate (GFR) is 10-70 mL/minute/1.73 m2, the total daily dose should be reduced by 25%. If the GFR is < 10, the total daily dose should be reduced by 50%. (5, 10, 23) With hemodialysis patients, the total daily dose should be reduced by 50% and the dose should be withheld until the dialysis treatment is completed. (23)

Tetracyclic

Caution is indicated in administering mirtazapine to patients with compromised renal function. Patients with a GFR of 11-39 mL/minute/1.73 m2 had reductions in mean oral clearance of approximately 30%. Patients with a GFR of < 10 had reductions in mean oral clearance of approximately 50%. (24)

Dosage in Hepatic Dysfunction

TCA

It is recommended that TCAs be used in lower dosages in patients with hepatic dysfunction. (56)

MAOI

MAOIs should probably not be used in patients with hepatic dysfunction, due to their increased side effects.

SSRI

Fluoxetine is metabolized in the liver. (17) A lower or less frequent dosage is recommended with fluoxetine in patients with hepatic insufficiency.

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)

Triazolopyridine

No adjustment of nefazodone is necessary in patients with moderate hepatic dysfunction. (55) Caution is warranted in patients with severe hepatic dysfunction because of nefazodone's altered pharmacokinetics.

Aminoketone

Bupropion is extensively metabolized and its metabolites are conjugated in the liver. (22) Patients with hepatic insufficiency should have therapy initiated at a reduced dosage and be closely monitored for toxic effects.

Phenylethylamine

The dosage of venlafaxine should be reduced by 25-50% depending on the degree of hepatic impairment. (5, 10, 23)

Tetracyclic

Oral clearance of single-dose mirtazapine is decreased by approximately 30% in patients with hepatic impairment. (24) Caution is indicated in administering mirtazapine to patients with compromised hepatic function.

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.

Cost

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.

Table 13. Comparative costs
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
88.02 Tofranil PM(r)
Nortriptyline 0.29-1.15 86.80 20 mg x 120 11.66 generic
118.58 Pamelor(r)
Desipramine 0.22-0.72 73.80 50 mg x 120 24.53 generic
114.34 Norpramin(r)
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
230.47 Desyrel(r)
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

Summary

The selection of an antidepressant should be based on the individual patient's tolerability and compliance factors, adverse event profiles, knowledge of drug pharmacokinetics, the presence of comorbid conditions, potential for drug interactions, long-term tolerability, previous response to therapy, and pharmacoeconomic considerations. 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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[dr. bob] Dr. Bob is Robert Hsiung, MD, dr-bob@uchicago.edu

Revised: November 19, 2001 ("tetracyclic")
URL: http://www.dr-bob.org/tips/antidepressants.html
Original copyright 1997 University of Chicago Hospitals.
Web page copyright 1997-2001 Robert Hsiung.