Chapter 17:  Antidepressant Agents

• Drug Treatment for clinical depression--Second generation drugs are preferred and include:

  • selective serotonin reuptake inhibitors (SSRIs)

  • trazodone (Desyrel)

  • bupropion (Wellbutrin)

  • venlafaxine (Effexor)

  • nefazodone (Serzone)

   

• At least five of the following symptoms must be present within a two week period. At least one symptoms must be depressed mood or loss of interest or pleasure.

  •  Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g. feels sad or empty) or observation made by others (e.g., appears tearful) Note: In children and adolescents, this can be irritable mood.

  •  Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day, as indicated by either subjective account or observation made by others).

  •  Significant weight loss (when not dieting) or weight gain (e.g., a change of more than 5% of body weight in a month) or decrease or increase in appetite nearly every day. Note: in children, consider failure to make expected weight gains.

  •  Insomnia or hypersomnia nearly every day.

  •  Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down).

  •  Fatigue or loss of energy nearly every day.

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

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

  •  Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan or a suicide attempt or specific plan for committing suicide.

[Source: Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC; America Psychiatric Association, 1994]; Boyer, W., and Nemeroff, C.B., Mood Disorders: Depression and Mania, In, Medicine for the Practicing Physician, (Hurst, J.W., editor-in-chief) Appleton and Lange, 1996, pp. 22-23

•  A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least one week (or any duration if hospitalization is necessitated)

•  During the period of mood disturbance, three (or more) of the following symptoms have persisted (for if the mood is only irritable) and have been present to a significant degree:

1.   Inflated self-esteem or grandiosity.

2.   Decreased need for sleep (e.g. feels rested after only 3 hours of sleep)

3.   More talkative than usual or pressure to keep talking.

4.   Flight of ideas or subjective experience that thoughts are racing.

5.   Distractibility.

6.   Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation.

7.   Excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g. engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments.

 Mood disturbances must be sufficient to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features.

•  Mania is a syndrome that may include

  •  sustained, abnormal, clear mood elevation

  •   extreme, unrealistic confidence

  •   acceleration of psychomotor function, including a significant decreased need for sleep, rapid thoughts and speech

•   Patient behaviors suggestive of mania include:

  • lack of sleeping

  • active all the time

  •  spending excessive amounts of money

  •  hypersexuality

  •  impatience

  •  feels that nothing is wrong.

• Drug Treatment for Mania

  • Lithium is the mainstay for treatment.

  • Adjunctive treatment may include:

    •   haloperidol (Haldol)

    •   benzodiazepines  

  • For patients not responding to lithium, valproic acid (Depakene, Depakote) or carbamazepine (Tegretol) may be effective. Valproic acid (Depakene, Depakote) is considered as effective as lithium in treating acute mania.

[Source: Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC; America Psychiatric Association, 1994]; Boyer, W., and Nemeroff, C.B., Mood Disorders: Depression and Mania, In, Medicine for the Practicing Physician, (Hurst, J.W., editor-in-chief) Appleton and Lange, 1996, pp. 22-23

• Tricyclic antidepressants (TCA)

• Monoamine oxidase inhibitors (MAOI)

• Second generation agents, including serotonin-specific reuptake inhibitors (SSRIs)

• Serotonin-Specific Reuptake Inhibitors (SSRIs)

  • fluoxetine (Prozac)

  • clomipramine (Anafranil)

  • sertraline (Zoloft)

  • paroxetine (Paxil)

• Second Generation Drugs (not including SSRIs)

  • amoxapine (Asendin)

  • bupropion (Wellbutrin)

  • nefazodone (Serzone)

  • trazodone (Desyrel)

• Older Agents (First Generation and MAO enzyme inhibitors)

  • Tricyclic antidepressants (TCAs)

    • amitriptyline (Elavil, Endep)

    • imipramine (Tofranil)

    • desipramine (Norpramin)

    • doxepin (Sinequan)

    • clomipramine (Anafranil, also a SSRI)

    • maprotiline (Ludiomil)

    • nortriptyline (Aventyl, Pamelor)

    • protriptyline (Vivactil)

  • Monoamine oxidase inhibitors (MAO-I's)

    • phenelzine (Nardil)

    • tranylcypromine (Parnate)

    • clorgyline (specific for MAO type A)

    • isocarboxazid

  • Other

    • mirtazapine (Temeron)

    • venlafaxine (Effexor)

Serotonin-Specific Reuptake Inhibitors and Atypical Antidepressants

• The SSRIs have an advantage over most other antidepressant drugs because they're less likely to cause important anticholinergic side effects or cardiovascular side effects.  Also, in the setting of overdosage, these agents tend to be less likely to cause death.  Examples of SSRIs in contemporary use include fluoxetine, paroxetine, sertraline,  fluvoxamine, citalopram along with its enantiomer escitalopram.¹

  •  An example of an atypical antidepressant is buproprion (generic, Wellbutrin).¹  Buproprion may exert its effect by means of the dopaminergic system, although actions may extend to the noradrenergic and nicotinic pathways.² Probably buproprion acts through inhibition of the dopamine reuptake system.³

Possible Mechanisms of Action of Antidepressant Drugs

• Tricyclic Antidepressants

  • 

• Tricyclic agents are thought to enhance the actions of biogenic amines by inhibiting reuptake which is the primary mechanism of termination of action.

• Imipramine (Tofranil), a prototypic tricyclic antidepressant blocks norepinephrine reuptake. Tricyclics with tertiary amine side chains also have effects on other neurotransmitters, like serotonin.

• Among the tricyclics, clomipramine (Anafranil) has prominent actions on the serotonin system and has been shown effective in treating obsessive compulsive disorder.

• Serotonin-Specific Reuptake Inhibitors (SSRIS)

  • 

• Fluoxetine (Prozac) and other inhibitors of serotonin reuptake are relatively selective in their effects, with little direct action at other neurotransmitter sites.

• Venlafaxine (Effexor) has actions at both serotonin and norepinephrine sites, with about five times greater selectivity for serotonin.

• Paroxetine (Paxil) has about ten times greater serotonin selectivity compared to norepinephrine.

• Generalizations

  •   Blockade of dopamine transport produces a stumulant effect.

  •   Inhibition of serotonin uptake may result in antidepressant effects.

  •   Inhibition of norepinephrine reuptake consistently produces an antidepressant action.

  •   Inhibition of these uptake systems may not be sufficient to cause the antidepressant effects since the time course of clinical antidepressant effects is much longer (weeks) compared to inhibition of blockade itself.

[Baldessarini, R. J., Drugs and the Treatment of Psychiatric Disorders: Depression and Mania In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, pp.436-438.

• Side effects for TCA, MAOI, and second generation drugs.

  • Serotonin-Specific Reuptake Inhibitors (SSRI's)

    • Adverse Effects

      • Most Common Adverse Effects:

        • Nausea

        • Headache

        •  Insomnia

        • Nervousness

        • Fatigue

        •  Sexual Dysfunction

      • Less common Adverse Effects:

        •  Inappropriate ADH secretion

        •  rashes

        • extrapyrmidal effects early in treatment akathisia. dystonia, oro-lingual dyskinesia

      • SSRI: Withdrawal Effects

        • Dizziness

        • Nausea

        • Parathesias

        • Palpitations

        • Tremor

        • Anxiety

        • Vivid dreams

  •  Tricyclic Antidepressants: Most Common Adverse Effects

    • Urinary retention

    • Constipation

    • Weight Gain

    • Sexual Dysfunction

    • Confusion/Delirium

    • Orthostatic Hypotension

  • MAO Inhibitors: Most Common Adverse Effects

    • Sleep disturbances

    • Orthostatic Hypotension

    • Weight Gain

    • Sexual Dysfunction

    • Drug/Food Interactions*

      • *Concurrent use of MAO inhibitors with serotonergic agents such as clomipramine, an SSRi or narcotics (merpidine) can cause a "serotonin syndrome" which includes hyperpyrexia, agitation, neuromuscular irritibility, hypotension, coma, and death.

  • Other Agents: Adverse Effects

    • Venlafaxine (Effexor): similar to SSRI, except at higher doses, a dose-dependent increase in diastolic blood pressure is seen

    • Bupropion (Wellbutrin): agitation, anxiety, insomnia, headache, nausea, and at high doses seizures (contraindicated in pateints who have an increased risk of seizure).

    • Trazodone (Desyrel) :common adverse effects: sedation, orthostatic hypotension, nausea; rare side effect: :priapism, sometimes leading to permanent loss of erectile function.

The Medical Letter on Drugs and Therapeutics, vol. 39 (issue 998) April 11, 1997, The Medical Letter, Inc., New Rochelle, N.Y.

Clinical advantages of serotonin-selective reuptake inhibitors (SSRI)

Considerations

• No conclusive evidence that any antidepressant acts faster or is substantially more effective than another.

•  However, there is a wide range of differences in:

  • side effects 

  • dangers of drug-drug interactions 

  • interactions with other illnesses 

  • toxicity in overdosage and dosing schedules 

Boyer, W. and Nemeroff, C. Mood Disorders: Depression and Mania, In, Medicine for the Practicing Physician, (Hurst, J.W., editor-in-chief) Appleton and Lange, 1996, p. 25.

• Basis for prescribing one antidepressant over another in a given patient

  • Overall Considerations

    • SSRIs (second generation drugs generally have: fewer side effects, decreased risk of drug-drug interactions, reduced chance of worsening other illnesses, and reduced toxicity in overdosage:

    [Medical Letter, vol 39, issue 998, April 11, 1997; Amseterdam, J and Hornig-Rohan, M, Psychiatr Clin North Am, 19:371, 1996; Robillard, M and Lieff, S, Can J Psychiatry, 40: 639, 1995]

    Boyer, W. and Nemeroff, C. Mood Disorders: Depression and Mania, In, Medicine for the Practicing Physician, (Hurst, J.W., editor-in-chief) Appleton and Lange, 1996, p. 25

    [Medical Letter, vol 39, issue 998, April 11, 1997; Amseterdam, J and Hornig-Rohan, M, Psychiatr Clin North Am, 19:371, 1996; Robillard, M and Lieff, S, Can J Psychiatry, 40: 639, 1995]

Antidepressants: Major Drug-Drug and Drug Food Interactions

• MAO Inhibitors:   Example: Phenelzine Sulfate (Nardil)

  •   Drug-Drug Interactions:

    • Tricyclic Antidepressants: Hyperpyrexia, Seizures

    • Fluoxetine (Prozac), Sertraline (Zoloft), Paroxetine (Paxil): Hyperthermia, Diaphoreis, Seizures, Delirium

    • Sympathomimetic Drugs (e.g. amphetamine, phenylephrine (Neo-Synephrine), phenylpropanolamine, guanethidine (Ismelin), reserpine): Hypertensive Crisis,

    • CNS Depressants: Additive Effects

    • Opioid Analgesics (particularly meperidine (Demerol)): Hypertensive crisis; circulatory collapse

    • Buspirone (BuSpar): Hypertension

    • General Anesthetics: Prolonged hypotensive and CNS depressive effects

  • Drug-Food Interactions: tyramine containing foods-- may cause Hypertensive Crisis.(if patient on MAOIs)

• Tricyclic Antidepressants:  Example: Imipramine Hydrochloride (Tofranil)

  • Drug-Drug Interactions

    •  MAO Inhibitors: Hypertensive Crisis, Tachycardia, Seizures

    •  Antihypertensive Medications: Potentiation of Orthostatic Hypotension,

    • CNS Depressants: Additive

    •  Sympathomimetics: Increased Cardiotoxicity,

    •   Cimetidine (Tagamet): Decreased liver metabolism resulting in higher imipramine levels

• Serotonin-Specific Reuptake Inhibitors (SSRIs):  Example: Fluoxetine Hydrochloride (Prozac)

  • Drug-Drug Interactions

    • Tryptophan: may cause agitation, restlessness;

    • MAO Inhibitors: Insufficient Data (1995)

    • Tricyclic Antidepressans may increase toxicity

Shannon, M.T., Wilson, B.A., Stang, C. L. In, Govoni and Hayes 8th Edition: Drugs and Nursing Implications Appleton & Lange, 1995, p.617

Symptoms of overdose and the treatments

Antidepressants: Management of Overdosage

Baldessarini, R.J., Drugs and the Treatment of Psychiatric Disorders: Depression and Manial In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.442- 443.

Antidepressant Classification

• Tricyclic antidepressants (TCAs)

  • Amitriptyline (Elavil, Endep)

    • Overview:

      • inhibits norepinephrine and serotonin reuptake

      • anticholinergic properties: greater than imipramine

      • antihistaminic properties

      • orthostatic hypotension due to alpha receptor blockade

      • sedation: greater than imipramine

      • mild analgesic

    • Clinical uses: 

      • endogenous depression

      • prophylaxis for migrane 

      • intractable pain 

      • eating disorder associated with depression 

      • sedative for non-depressed patients

  • Imipramine (Tofranil)

    • Overview:

      • inhibits norepinephrine and serotonin reuptake

      • anticholinergic properties: greater than imipramine

      • antihistaminic properties

      • orthostatic hypotension due to alpha receptor blockade

      • sedation: greater than imipramine

      • mild analgesic

    • Clinical uses: 

      •  endogenous depression

      •  occasionally reactive depression

      •  treatment of enuresis in children older than six

      • alcoholism 

      • cocaine withdrawal 

      • attention deficit disorders 

      • with amphetamine or methyphenidate for narcolepsy 

      • phobic anxiety 

      • panic disorder 

      • agoraphobia 

      • obsessive compulsive disorder

    •  Adverse Effects

      • Central Nervous System: sedation, drowsiness, lowering of seizure threshold

      • Cardiovascular System: orthostatic hypotension, arrhythmias, hypertension/hypotension, heart block, ECG changes, myocardial infarction.

      • Endocrine: gynecomostia, testicular swelling, ejaculatory and erectile disturbances

      • Ocular: Blurred vision, mydriasis

      • GI: Dry mouth, constipation

      • GU: Urinary retention

      • Hematologic: bone marrow suppression, agranulocytosis

    •  Drug Interactions

      • MAO Inhibitors: hyperpyrexic crisis, seizures

      • Antihypertensive agents: potentiation of postural hypotension

      • CNS depression: additive

      • Norepinephrine: increase in cardiac toxicity

      • Methylphenidate (Ritalin) inhibits imipramine metabolism, which may lead to imipramine toxicity

Shannon, M.T., Wilson, B.A., Stang, C. L. In, Govoni and Hayes 8th Edition: Drugs and Nursing Implications Appleton & Lange, 1995, pp. 616-619

• Desipramine (Norpramin)

• Doxepin (Sinequan)

• Clomipramine (Anafranil), also a SSRI

  • Overview

    • inhibits norepinephrine and serotonin reuptake

    • anticholinergic properties

    • hypotension, tachycardia

  • Clinical Uses:

    • obsessive-compulsive disorder

    • panic disorder/agoraphobia

    • agoraphobia

  • Adverse Effects

    • Central Nervous System: mania, tremor, dizziness, neuroleptic malignant syndrome.

    • Cardiovascular System: orthostatic hypotension, tachycardia

    • Endocrine: galactorrhea, hyperprolactinemia, amorrhea, weight gain

    • GI: Dry mouth, constipation

    • GU: delayed ejaculation, anorgasmia

    • Hematologic:leukopenia, agranulocytosis, thrombocytopenia, anemia

  • Drug Interactions

    •  MAO Inhibitors: hyperpyrexic crisis, seizures

    •  Antihypertensive agents: potentiation of postural hypotension

    • CNS depression: additive

    •  Norepinephrine: increase in cardiac toxicity

    •  Methylphenidate inhibits imipramine metabolism, which may lead to imipramine toxicity

• maprotiline (Ludiomil)

• nortriptyline (Aventyl, Pamelor)

• protriptyline (Vivactil)

• Monoamine oxidase inhibitors (MAO-Is)

  • Phenelzine (Nardil)

    • Overview:

      • Hydrazine MAO inhibitor with amphetamine-like activity

      • Termination of drug action requires new MAO synthesis

      • May cause Hypertensive crisis

    • Clinical Uses

      • treatment of endogenous depression

      • management of depressive phase of bipolar disorder

      • treatment of severe reactive depression not responsive to other drugs.

    • Some Adverse Effects 

      • constipation

      • dry mouth

      • orthostatic hypotension

      • insomnia

      • nausea

      • anorexia

      • hypertensive crisis

    • Drug-Drug & Drug-Food Interactions

      • Tricyclic Antidepressants: hyperpyrexia, seizures 

      • SSRI's (fluoxetine, sertraline, paroxetine, etc): hyperthermia (serotonin syndrome), diaphoresis, tremors, seizures, delirium 

      • Sympathomimetic drugs (amphetamine, phenylpropanolamine, guanetidine, reserpine, phenylephrine): hypertensive crisis 

      • CNS depressants: Additive effects

      • Opiate Analgesics (especially meperidine): hypertensive crisis, circulatory collapse 

      • Buspirone (BuSpar): hypertension

      • General Anesthetics: prolonged hypotension and CNS depression

      • Dopamine, L-DOPA, methyldopa, tryptophan: headache, hypertension, hyperexciability: 

      • Metrizamide: increased seizure risk 

      • FOOD: aged meats, cheezes, anchovies, sausages, figs, bananas, avacados, chocolate, soy sausce, fava beans, bean curd, natural yogurt, [tyramine-containing foods): HYPERTENSIVE CRISIS  (Shannon, M.T., Wilson, B.A., Stang, C. L. In, Govoni and Hayes 8th Edition: Drugs and Nursing Implications Appleton & Lange, 1995, pp. 904-905)

  • tranylcypromine (Parnate)

  • clorgyline (specific for MAO type A)

  • isocarboxazid

• Second Generation Drugs (not including SSRIs)

  • Amoxapine (Asendin) (Shannon, M.T., Wilson, B.A., Stang, C. L. In, Govoni and Hayes 8th Edition: Drugs and Nursing Implications Appleton & Lange, 1995, pp. 125-126.)

    • Overview:

      • dopamine receptor blocker

      • inhibits presynaptic neuronal norepinephrine and serotonin reuptake

    • Clinical Uses

      •  endogenous depression

      •  neurotic depression with anxiety

    •  Adverse Effects

      • Central Nervous System: drowsiness, sedation (less than TCA's)

      •  Cardiovascular System: orthostatic hypotension, arrhythmias

      •  GI: constipation, diarrhea, flatulence, dry mouth

      •  Endocrine effects related to amoxipine's structural similarity to the antipsychotic agent loxapine

    •  Drug Interactions

      • Antihypertensives: decreased response to antihypertensive

      • CNS Depressants: increased

  • bupropion (Wellbutrin)

  • nefazodone (Serzone)

  • trazodone (Desyrel)

• Serotonin-Specific Reuptake Inhibitors (SSRIs)

  • Fluoxetine (Prozac) [Shannon, M.T., Wilson, B.A., Stang, C. L. In, Govoni and Hayes 8th Edition: Drugs and Nursing Implications Appleton & Lange, 1995, pp. 535]

    • Overview:

      • inhibits presynaptic neuronal serotonin reuptake

    • Clinical Uses:

      • endogenous depression

      • obsessive-compulsive disorder

      • obseity

      • bulimia nervosa

    • Adverse Effects:

      • Central Nervous System: headache, nervousness, anxiety, insomnia

      • Cardiovascular System: palpitations, chest pain

      • GI: nausea, diarrhea

      • GU: Urinary retention

    •  Drug Interactions

      • MAO Inhibitors: use cautiously (hyperthermia (serotonin syndrome), diaphoresis, tremors, seizures, delirium)

      • Tricyclic Antidepressants: Increased toxicity

  • Clomipramine (Anafranil) -- see above

  • Sertraline (Zoloft)

  • Paroxetine (Paxil)

• Other

  • Mirtazapine (Temeron)

  • Venlafaxine (Effexor)

1. Eisendrath, SJ and Lichtmacher, JE, Psychiatric Disorders, in 2008 Current Medical Diagnosis & Treatment (McPhee, SJ, Papadakis, MA, eds, Tierney, LM, Senior editor) chapter 25, pp.  923-928.  47th edition, 2008.

2. Ascher, JA, Cole, JO, Colin, JN, et al. Buproprion: a review of its mechanism of antidepressant activity. J. Clin. Psychiatry 1995; 59:112-115.

3. Horst, WD. Preskorn, SH. Mechanism of action and clinical characteristics of three atypical antidepressants: venlafaxine, nefazodone, buproprion. J. Affect Disord.  1998; 51:237-254.