|
Mixed Reuptake and Neuroreceptor Antagonists[]
- Amitriptyline(Elavil)
- Amoxapine (Ascendin )
- Clomipramine (Anafranil)
- Doxepin (Sinequan)
- Imipramine (Tofranil-PM)
- Trimipramine (Surmontil)
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|
Norepinephrine Selective Reuptake Inhibitors (NSRIs)[]
- Desipramine (Norpramin)
- Maprotiline (Ludiomil)
- Nortriptyline (Pamelor, Aventyl)
- Protriptyline (Vivactil)
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|
Serotonin Selective Reuptake Inhibitors (SSRIs)
- Citalopram (Celexa)
- Fluoxetine (Prozac)
- Fluvoxamine (Luvox)
- Paroxetine (Paxil)
- Sertraline (Zoloft)
|
|
Serotonin and Norepinephrine
Reuptake Inhibitor (SNRI)[§]
|
|
Serotonin -2A (5-HT2A) Receptor Blocker
and Weak Serotonin Uptake Inhibitor[||]
- Nefazodone (Serzone)
- Trazodone (Desyrel)
|
|
Serotonin (5-HT2A and 2C) and
a-2 Norepinephrine Receptor Blocker[||]
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Dopamine and Norepinephrine Reuptake Inhibitors
- Bupropion (Wellbutrin, Wellbutrin SR, Zyban Sustained-Release)
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Monoamine Oxidase Inhibitors (MAOIs)[Ά]
- Phenelzine (Nardil)
- Tranylcypromine (Parnate)
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Abbreviations: 5-HT, 5-hydroxytryptamine (serotonin). |
|
*The presumptive mechanism of action for each drug is based on the preclinical pharmacology of the drug and the fact that it and/or its active metabolites reaches sufficient concentration in vivo to affect this site of action, given its in vitro potency.
All of these drugs are tertiary amine tricyclic antidepressants (TCAs) except amoxapine.
All of these drugs are secondary amine TCAs except maprotiline. There are nontricyclic NSRIs available in other parts of the world, such as reboxetine. Those drugs share the ability to inhibit norepinephrine uptake with the secondary amine TCAs and maprotiline but do not carry the risk of serious toxicity even after a substantial overdose.
§At present, venlafaxine is the only member of this class available in the United States although several others are in various stages of clinical testing.
||Both nefazodone and mirtazapine also have other mechanisms of action that are engaged at concentrations which occur under clinically relevant dosing guidelines (see Table 6.2).
ΆOnly irreversible and nonselective monoamine oxidase inhibitors (MAOIs) are available in the United States, but selective and reversible MAOIs are marketed elsewhere in the world.
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|
Mechanism of Action |
Amitriptyline |
Desipramine |
Sertraline |
Venlafaxine |
Nefazodone |
Mirtazapine |
Bupropion |
Tranylcy-
promine |
|
Histamine-1 receptor blockade |
Yes[] |
No |
No |
No |
No |
Yes[] |
No |
No |
|
Acetylcholine receptor blockade |
Yes |
No |
No |
No |
No |
No |
No |
No |
|
NE uptake inhibition |
Yes |
Yes |
No |
Yes |
No |
No |
Yes |
No |
|
5-HT2A receptor blockade |
Yes |
No |
No |
No |
Yes[] |
Yes |
No |
No |
|
alpha-1 NE receptor blockade |
Yes |
No |
No |
No |
Yes |
No |
No |
No |
|
5-HT uptake inhibition |
Yes |
No |
Yes |
Yes[] |
Yes |
No |
No |
No |
|
alpha-2 NE receptor blockade |
No |
No |
No |
No |
No |
Yes |
No |
No |
|
5-HT2C receptor blockade |
No |
No |
No |
No |
No |
Yes |
No |
No |
|
5-HT3 receptor blockade |
No |
No |
No |
No |
No |
Yes |
No |
No |
|
Fast Na[+ ]channels inhibition |
No |
No |
No |
No |
No |
No |
No |
No |
|
Dopamine uptake inhibition |
No |
No |
No |
No |
No |
No |
Yes |
No |
|
Monoamine oxidase inhibition |
No |
No |
No |
No |
No |
No |
No |
Yes |
|
Abbreviations: NE, norepinephrine; 5-HT, 5-hydroxytryptamine (serotonin); Na[+], sodium. |
|
* Amitriptyline represents the mixed reuptake and neuroreceptor blocking class, desipramine -- norepinephrine selective reuptake inhibitors, sertraline -- serotonin selective reuptake inhibitors, venlafaxine -- serotonin and norepinephrine reuptake inhibitors, nefazodone -- 5-HT2A and weak serotonin uptake inhibitors, and mirtazapine -- specific serotonin and norepinephrine receptor blockers, bupropion -- dopamine and norepinephrine uptake inhibitor. Monoamine oxidase inhibitors (MAOIs) do not directly share any mechanism of action with other classes of antidepressants, although they affect dopamine, norepinephrine, and serotonin neurotransmission via their effects on monoamine oxidase.
The effects of these various antidepressants are listed using a binary (yes/no) approach for simplicity and clinical relevance. The issue for clinician and patient is whether the effect is expected under usual dosing conditions. A "yes" means that the usual patient on the usually effective antidepressant dose of the drug achieves concentrations of parent drug and/or metabolites that should engage that specific target to a physiologically/clinically significant extent given the in vitro affinity of the parent drug and/or metabolites for that target. If the affinity for another target is within an order of magnitude of desired target, then that target is likely also affected to a physiologically relevant degree. For example, under usual dosing conditions, amitriptyline achieves concentrations that engage the norepinephrine uptake pump. At such concentrations, it also substantially blocks histamine-1 and muscarinic acetylcholine receptors since it has even more affinity for those targets than it does for the norepinephrine uptake pump. Since the binding affinity of amitriptyline for the 5-HT2A and alpha-1 norepinephrine receptors and the serotonin uptake pump are within an order of magnitude of its affinity for the norepinephrine uptake pump, amitriptyline at usual therapeutic concentrations for antidepressant efficacy will also affect those targets. On the other hand, amitriptyline will not typically affect Na[+] fast channels at usual therapeutic concentrations because there is more than an order of magnitude (ie, > 10-fold) separation between its effects on this target versus norepinephrine uptake inhibition. Nevertheless, an amitriptyline overdose can result in concentrations which engage this target. That fact accounts for the narrow therapeutic index of the tricyclic antidepressants (TCAs) and is the reason therapeutic drug monitoring to detect unusually slow clearance is a standard of care when using such drugs.
Most potent effect (ie, effect that occurs at lowest concentration). See next footnote for further explanation.
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|
The binding affinities of all drugs listed in the table (except mirtazapine) are based on the work of Cusack et al and Bolden-Watson and Richelson. Information on the binding affinities of mirtazapine (including affinities for 5-HT2A and 5-HT3 receptors) is based on the work of de Boer et al. Although the publications by the Richelson group did not include values for the 5-HT2A and 5-HT3 receptors or the other antidepressants, Elliot Richelson of the Mayo Clinic in Jacksonville, Florida (personal communication) confirmed that the other antidepressants would be unlikely to affect these receptors under usual dosing conditions. |
|
Adapted from: Bolden-Watson C, Richelson E. Life Sci. 1993;52:1023-1029; Cusack B, et al. Psychopharmacology. 1994;114:559-565; de Boer T, et al. Neuropharmacology. 1988;27:399-408; de Boer T, et al. Human Psychopharmacology. 1995;10:107S-118S; and Frazer A. J Clin Psychiatry. 1997;58:9-25. |
|
Site of Action |
Consequence of Blockade |
|
Histamine-1 receptor |
Sedation, antipruritic effect |
|
Muscarinic acetylcholine receptor |
Dry mouth, constipation, sinus tachycardia, memory impairment |
|
NE uptake pump |
Antidepressant efficacy, \ blood pressure, tremors, diaphoresis |
|
5-HT2A receptor |
Antidepressant efficacy, \ rapid eye movement sleep, antianxiety efficacy, anti-extrapyramidal symptoms |
|
alpha-1 NE receptor |
Orthostatic hypotension, sedation |
|
5-HT2 uptake pump |
Antidepressant efficacy, nausea, loose stools, insomnia, anorgasmia |
|
alpha-2 NE receptor |
Antidepressant efficacy, arousal, \ libido |
|
5-HT2C receptor |
Antianxiety efficacy, \ appetite, [rparenbot] motor restlessness |
|
5-HT3 receptor |
Antinauseant |
|
Fast Na[+] channels |
Delayed repolarization leading to arrhythmia, seizures, delirium |
|
Dopamine uptake pump |
Antidepressant efficacy, euphoria, abuse potential, antiparkinson activity, aggravation of psychosis |
|
Monoamine oxidase |
Antidepressant activity, decreased blood pressure* |
|
Abbreviations: NE, norepinephrine; 5-HT, 5-hydroxytryptamine (serotonin); Na[+], sodium. |
|
* Hypertensive crisis (ie, markedly elevated blood pressure) and serotonin syndrome can occur when monoamine oxidase inhibitors are combined with noradrenergic and serotonin agonists, respectively. |
|
Adapted from: Preskorn SH. Clinical Pharmacology of Selective Serotonin Reuptake Inhibitors. Caddo, Okla: Professional Communications, Inc; 1996;48-49. |
|
Adverse Effect |
Citalopram
(n=1063, n=446)[a] |
Fluoxetine
(n=1730, n=799)[a] |
Fluvoxamine
(n=222, n=192)[a] |
Paroxetine
(n=421, n=421)[a] |
Sertraline
(n=861, n=853)[a] |
|
Anorexia |
2 |
7.2 |
8.6 |
4.5 |
1.2 |
|
Confusion[b] |
NA |
1.5 |
NA |
1 |
0.8 |
|
Constipation |
< placebo |
1.2 |
11.2 |
5.2 |
2.1 |
|
Diarrhea[c] |
3 |
5.3 |
- 0.4 |
4 |
8.4 |
|
Dizziness[d] |
< placebo |
4 |
1.3 |
7.8 |
5 |
|
Drowsiness[e] |
8 |
5.9 |
17.2 |
14.3 |
7.5 |
|
Dry mouth |
6 |
3.5 |
1.8 |
6 |
7 |
|
Dyspepsia |
1 |
2.1 |
3.2 |
0.9 |
3.2 |
|
Fatigue[f] |
2 |
5.6 |
6.2 |
10.3 |
2.5 |
|
Flatulence |
NA |
0.5 |
NA |
2.3 |
0.8 |
|
Frequent micturition |
NA |
1.6 |
0.6 |
2.4 |
0.8 |
|
Headache |
< placebo |
4.8 |
2.9 |
0.3 |
1.3 |
|
Increased appetite |
NA |
NA |
NA |
NA |
NA |
|
Insomnia |
1 |
6.7 |
4 |
7.1 |
7.6 |
|
Nausea[g] |
8 |
11 |
25.6 |
16.4 |
14.3 |
|
Nervousness[h] |
3 |
10.3 |
7.6 |
4.9 |
4.4 |
|
Palpitations[i] |
< placebo |
- 0.1 |
NA |
1.5 |
1.9 |
|
Paresthesia[j] |
NA |
- 0.3 |
NA |
2.1 |
1.3 |
|
Rash[k] |
NA |
0.9 |
NA |
1 |
0.6 |
|
Respiratory[l] |
8 |
5.8 |
- 1.3 |
0.8 |
0.8 |
|
Sweating |
2 |
4.6 |
- 1.3 |
8.8 |
5.5 |
|
Tremors |
2 |
5.5 |
6.1 |
6.4 |
8 |
|
Urinary retention[m] |
< placebo |
NA |
NA |
2.7 |
0.9 |
|
Vision disturbances |
< placebo |
1 |
0 |
2.2 |
2.1 |
|
Weight gain |
NA |
NA |
NA |
NA |
NA |
|
Abbreviations: NA, not available. |
|
* Data for fluoxetine, paroxetine and sertraline is from Preskorn SH. J Clin Psychiatry. 1995;56(suppl 6):12-21; data for fluvoxamine is from Compendium of Pharmaceuticals and Specialties. 30th ed. 1995:737-738; data for citalopram is from Forest Pharmaceuticals, Inc. prescribing information; 1998. Incidence of each respective adverse effect for patients taking each drug minus the incidence for each drug's parallel placebo control in double-blind placebo-controlled studies.
[a] The first value is the number of patients on that medication, while the second represents those treated in the parallel, placebo group.
[b] Includes decreased concentration, memory impairment, abandoned thinking concentration.
[c] Includes gastroenteritis.
[d] Includes lightheadedness, postural hypotension, hypotension.
[e] Includes somnolence, sedation, and drugged feeling.
[f] Includes asthenia, myasthenia, psychomotor retardation.
[g] Includes vomiting.
[h] Includes anxiety, agitation, hostility, akathisia, central nervous system stimulation.
[i] Includes tachycardia, arrhythmias.
[j] Includes sensation disturbances, hypesthesia.
[k] Includes pruritus.
[l] Includes respiratory disorder, upper respiratory infection, flu, dyspnea, pharyngitis, sinus congestion, oropharynx disorder, fever and chill.
[m] Includes micturition disorder, difficulty with micturition, and urinary hesitancy.
|
|
Adverse Effect |
Bupropion
(n=323, n=185)[a] |
Imipramine
(n=367, n=672)[a] |
Mirtazapine
(n=453, n=361)[a] |
Nefazodone
(n=393, n=394)[a] |
Venlafaxine-IR
(n=1033, n=609)[a] |
Venlafaxine-XR
(n = 357, n = 285)[a] |
|
Anorexia |
- 0.1 |
NA |
NA |
NA |
9 |
4 |
|
Confusion[b] |
2.8 |
NA |
2 |
9 |
1 |
2 |
|
Constipation |
8.7 |
17.4 |
6 |
6 |
8 |
3 |
|
Diarrhea[c] |
- 1.8 |
- 2.7 |
< placebo |
1 |
1 |
< placebo |
|
Dizziness[d] |
6.8 |
22.7 |
4 |
23 |
12 |
11 |
|
Drowsiness[e] |
0.3 |
12 |
36 |
11 |
14 |
9 |
|
Dry mouth |
9.2 |
47.1 |
10 |
12 |
11 |
6 |
|
Dyspepsia |
0.9 |
NA |
< placebo |
2 |
1 |
< placebo |
|
Fatigue[f] |
- 3.6 |
7.6 |
3 |
7 |
6 |
1 |
|
Flatulence |
NA |
NA |
< placebo |
NA |
1 |
1 |
|
Frequent micturition |
0.3 |
NA |
1 |
1 |
1 |
NA |
|
Headache |
3.5 |
- 8.7 |
< placebo |
3 |
1 |
< placebo |
|
Increased appetite |
NA |
NA |
15 |
NA |
1 |
2 |
|
Insomnia |
5.3 |
0.4 |
< placebo |
2 |
8 |
6 |
|
Nausea[g] |
4 |
1.3 |
< placebo |
11 |
26 |
21 |
|
Nervousness[h] |
13.9 |
3.6 |
< placebo |
NA |
12 |
7 |
|
Palpitations[i] |
4.7 |
NA |
< placebo |
NA |
2 |
< placebo |
|
Paresthesia[j] |
0.8 |
NA |
NA |
2 |
1 |
NA |
|
Rash[k] |
3.7 |
NA |
NA |
2 |
1 |
NA |
|
Respiratory[l] |
- 2.5 |
- 2.3 |
3 |
9 |
NA |
1 |
|
Sweating |
7.7 |
11.2 |
< placebo |
NA |
9 |
11 |
|
Tremors |
13.5 |
10 |
1 |
1 |
4 |
3 |
|
Urinary retention[m] |
- 0.3 |
4 |
NA |
1 |
2 |
NA |
|
Vision disturbances |
4.3 |
5.4 |
< placebo |
12 |
4 |
4 |
|
Weight gain |
NA |
NA |
10 |
NA |
NA |
NA |
|
Abbreviations: IR, immediate release; XR, extended release; NA, not available. |
|
* Data from Preskorn SH. J Clin Psychiatry. 1995;56(suppl 6):12-21, and Physician's Desk Reference; 1999:2147-2149, 3298-3302.
[a] The first value is the number of patients on that medication, while the second represents those treated in the parallel, placebo group.
[b] Includes decreased concentration, memory impairment, abandoned thinking concentration.
[c] Includes gastroenteritis.
[d] Includes lightheadedness, postural hypotension, hypotension.
[e] Includes somnolence, sedation, and drugged feeling.
[f] Includes asthenia, myasthenia, psychomotor retardation.
[g] Includes vomiting.
[h] Includes anxiety, agitation, hostility, akathisia, central nervous system stimulation.
[i] Includes tachycardia, arrhythmias.
[j] Includes sensation disturbances, hypesthesia.
[k] Includes pruritus.
[l] Includes respiratory disorder, upper respiratory infection, flu, dyspnea, pharyngitis, sinus congestion, oropharynx disorder, fever and chill.
[m] Includes micturition disorder, difficulty with micturition, and urinary hesitancy.
|
|
CYP 1A2 |
|
|
Antidepressants |
Amitriptyline, clomipramine, imipramine |
|
Antipsychotics |
Clozapine*, olanzapine*, thioridazine* |
|
beta-Blockers |
Propanolol |
|
Opiates |
Methadone* |
|
Miscellaneous |
Caffeine*, paracetamol, tacrine*, theophylline*, R-warfarin* |
|
CYP 2C9 /10 |
Phenytoin*, S-warfarin*, tolbutamide* |
|
CYP 2C19 |
|
|
Antidepressants |
Citalopram*, clomipramine, imipramine |
|
Barbiturates |
Hexobarbital, mephobarbital, S-mephenytoin* |
|
beta-Blockers |
Propranolol |
|
Benzodiazepines |
Diazepam |
|
CYP 2D6 |
|
|
Antiarrhythmics |
Encainide*, flecainide*, mexiletine, propafenone |
|
Antipsychotics |
Haloperiodol (minor), molindone, perphenazine*, risperidone*, thioridazine (minor) |
|
beta-Blockers |
Alprenolol, bufuralol, metoprolol*, propranolol, timolol |
|
Miscellaneous |
Debrisoquin*, 4-hydroxyamphetamine, perhexiline*, phenformin, sparteine* |
|
Opiates |
Codeine*, dextromethorphan*, ethylmorphine |
|
SSRIs |
Fluoxetine, N-desmethylcitalopram, paroxetine* |
|
TCAs |
Amitriptyline*, clomipramine*, desipramine*, imipramine*, N-desmethylclomipramine |
|
Other antidepressants |
Venlafaxine*, mCPP metabolite of nefazodone* and trazodone* |
|
CYP 3A3 /4 |
|
|
Analgesics |
Acetaminophen, alfentanil |
|
Antiarrhythmics |
Amiodarone, disopyramide, lidocaine, propafenone, quinidine |
|
Anticonvulsants |
Carbamazepine*, ethosuximide |
|
Antidepressants |
Amitriptyline, clomipramine, imipramine, nefazodone*, sertraline*,
o-desmethylvenlafaxine* |
|
Antiestrogens |
Docetaxol, paclitaxel, tamoxifen* |
|
Antihistamines |
Astemizole*, loratadine*, terfenadine* |
|
Antipsychotics |
Quetiapine*, clozapine |
|
Benzodiazepines |
Alprazolam*, clonazepam, diazepam, midazolam*, triazolam* |
|
Calcium channel blockers |
Diltiazem*, felodipine*, nicardipine, nifedipine*, niludipine, manidipine, nisoldipine, nitrendipine, verapamil* |
|
Immunosuppressants |
Cyclosporine*, tacrolimus (FK506-macrolide) |
|
Local anesthetics |
Cocaine, lidocaine |
|
Macrolide antibiotics |
Clarithromycin, erythromycin, acetyloleandomycin |
|
Steroids |
Androstenedione, cortisol*, dehydroepiandrosterone 3-sulfate, dexamethasone, estrogen*, testosterone*, estradiol*, ethinylestradiol, progesterone |
|
Miscellaneous |
Benzphetamine, cisapride*, dapsone*, lovastatin, omeprazole (sulfonation) |
|
Abbreviations: CYP, cytochrome P450 enzyme; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressants. |
|
* Principal CYP enzyme |
|
NOTE : Such lists are not comprehensive since the CYP enzyme(s) responsible for biotransformation is known for only approximately 20% of marketed drugs. The reason is that many drugs were developed before the necessary knowledge and technology existed. Some drugs are listed under more than one CYP enzyme. That does not necessarily mean that each of these enzymes contributes equally to the elimination of the drug. One enzyme may be principally responsible based on substrate affinity and capacity and abundance of the enzyme. |
|
Adapted from: Preskorn SH. Clinical Pharmacology of Selective Serotonin Reuptake Inhibitors. Caddo, Okla: Professional Communications, Inc; 1996:158-159. |
Appetite