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Drug Treatment of Depression

By

William Coryell

, MD, Carver College of Medicine at University of Iowa

Last full review/revision Aug 2021| Content last modified Aug 2021
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Antidepressants and suicide risk

Patients and their loved ones should be warned that a few patients may seem more agitated, depressed, and anxious within a week of starting an antidepressant or increasing the dose; symptoms that worsen with treatment should be reported to the physician. This situation should be closely monitored because some patients, especially younger children and adolescents, become increasingly suicidal if agitation, increased depression, and anxiety are not detected and rapidly treated.

Several analyses of the Food and Drug Administration (FDA) database of industry-sponsored trials led to a black box warning that antidepressants in general are associated with an increased risk of emergence of suicidal ideas and suicide attempts in patients aged 24 years. Subsequent analyses of FDA and other data have cast doubt on this conclusion (1 General reference Several drug classes and drugs can be used to treat depression: Selective serotonin reuptake inhibitors (SSRIs) Serotonin modulators (5-HT2 blockers) Serotonin-norepinephrine reuptake inhibitors... read more ).

Evidence suggests that risk of suicidality does not differ among classes of antidepressants, including SSRIs, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, and MAOIs. Evidence is not adequate to determine quantitatively the risk associated with specific antidepressants.

General reference

  • 1. Dragioti E, Solmi M, Favaro A, et al: Association of antidepressant use with adverse health outcomes: A systematic umbrella review. JAMA Psychiatry 76 (12):1241-1255, 2019. doi: 10.1001/jamapsychiatry.2019.2859

Selective Serotonin Reuptake Inhibitors (SSRIs)

These drugs prevent reuptake of serotonin (5-hydroxytryptamine [5-HT]). SSRIs include citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and vilazodone. Although these drugs have the same mechanism of action, differences in their clinical properties make selection important. Selective serotonin reuptake inhibitors (SSRIs) have a wide therapeutic margin; they are relatively easy to administer, with little need for dose adjustment (except for fluvoxamine).

By preventing reuptake of 5-HT presynaptically, SSRIs result in more 5-HT to stimulate postsynaptic 5-HT receptors. SSRIs are selective to the 5-HT system but not specific for the different 5-HT receptors. They stimulate 5-HT1 receptors, with antidepressant and anxiolytic effects, but they also stimulate 5-HT2 receptors, commonly causing anxiety, insomnia, and sexual dysfunction, and 5-HT3 receptors, commonly causing nausea and headache. Thus, SSRIs can paradoxically relieve and cause anxiety.

Sexual dysfunction (especially difficulty achieving orgasm but also decreased libido Libido There are 4 main components of male sexual function: Libido Erection Ejaculation Orgasm read more and erectile dysfunction Erectile Dysfunction Erectile dysfunction is the inability to attain or sustain an erection satisfactory for sexual intercourse. Most erectile dysfunction is related to vascular, neurologic, psychologic, and hormonal... read more ) occurs in one third or more of patients. Some SSRIs cause weight gain. Others, especially fluoxetine, may cause anorexia in the first few months. SSRIs have few anticholinergic, adrenolytic, and cardiac conduction effects. Sedation is minimal or nonexistent, but in the early weeks of treatment, some patients tend to be sleepy during the day. Loose stools or diarrhea occurs in some patients.

Drug interactions are relatively uncommon; however, fluoxetine, paroxetine, and fluvoxamine can inhibit cytochrome P-450 (CYP450) isoenzymes, which can lead to serious drug interactions. For example, these drugs can inhibit the metabolism of certain beta-blockers, including propranolol and metoprolol, potentially resulting in hypotension and bradycardia.

Discontinuation symptoms (eg, irritability, anxiety, nausea) can occur if the drug is stopped abruptly; such effects are less likely with fluoxetine.

Modulators (5-HT2 Blockers)

These drugs block primarily the 5-HT2 receptor and inhibit reuptake of 5-HT and norepinephrine. Serotonin modulators include

  • Trazodone

  • Mirtazapine

Serotonin modulators have antidepressant and anxiolytic effects but do not cause sexual dysfunction.

Mirtazapine is a 5-HT antagonist and blocks alpha-2 adrenergic autoreceptors, as well as 5-HT2 and 5-HT3 receptors. The result is increased serotonergic function and increased noradrenergic function without sexual dysfunction or nausea. It has no cardiac adverse effects, has minimal interaction with drug-metabolizing liver enzymes, and is generally well-tolerated, although it does cause sedation and weight gain, mediated by H1 (histamine) blockade.

Serotonin-Norepinephrine Reuptake Inhibitors

However, their toxicity approximates that of selective serotonin reuptake inhibitors (SSRIs). Nausea is the most common problem during the first 2 weeks; modest dose-dependent increases in blood pressure (BP) occur with high doses. Discontinuation symptoms (eg, irritability, anxiety, nausea) often occur if the drug is stopped suddenly.

Duloxetine resembles venlafaxine in effectiveness and adverse effects.

Norepinephrine-Dopamine Reuptake Inhibitor

By mechanisms not clearly understood, this class of drug favorably influences dopaminergic and noradrenergic function and does not affect the 5-HT system.

Bupropion is currently the only drug in this class. It can help depressed patients with concurrent attention-deficit/hyperactivity disorder Attention-Deficit/Hyperactivity Disorder (ADD, ADHD) Attention-deficit/hyperactivity disorder (ADHD) is a syndrome of inattention, hyperactivity, and impulsivity. The 3 types of ADHD are predominantly inattentive, predominantly hyperactive/impulsive... read more or cocaine use disorder Cocaine Cocaine is a sympathomimetic drug with central nervous system stimulant and euphoriant properties. High doses can cause panic, schizophrenic-like symptoms, seizures, hyperthermia, hypertension... read more and those trying to stop smoking. Bupropion causes hypertension in a very few patients but has no other effects on the cardiovascular system. Bupropion can cause seizures in 0.4% of patients taking doses > 150 mg three times a day (or > 200 mg sustained-release [SR] twice a day or > 450 mg extended-release [XR] once a day); risk is increased in patients with bulimia Bulimia Nervosa Bulimia nervosa is characterized by recurrent episodes of binge eating followed by some form of inappropriate compensatory behavior such as purging (self-induced vomiting, laxative or diuretic... read more . Bupropion does not have sexual adverse effects and interacts little with coadministered drugs, although it does inhibit the CYP2D6 hepatic enzyme. Agitation, which is common, is considerably attenuated by using the SR or XR form.

Heterocyclic Antidepressants

This group of drugs, once the mainstay of treatment, includes tricyclic (tertiary amines amitriptyline and imipramine and their secondary amine metabolites nortriptyline and desipramine), modified tricyclic, and tetracyclic antidepressants.

Acutely, heterocyclic antidepressants increase the availability of primarily norepinephrine and, to some extent, 5-HT by blocking reuptake in the synaptic cleft. Long-term use downregulates alpha-1 adrenergic receptors on the postsynaptic membrane—a possible final common pathway of their antidepressant activity.

Although effective, these drugs are now rarely used because overdose causes toxicity and they have more adverse effects than other antidepressants. The more common adverse effects of heterocyclics are due to their muscarinic-blocking, histamine-blocking, and alpha-1 adrenolytic actions. Many heterocyclics have strong anticholinergic properties and are thus unsuitable for older patients and those with benign prostatic hypertrophy Benign Prostatic Hyperplasia (BPH) Benign prostatic hyperplasia (BPH) is nonmalignant adenomatous overgrowth of the periurethral prostate gland. Symptoms are those of bladder outlet obstruction—weak stream, hesitancy, urinary... read more , glaucoma Overview of Glaucoma Glaucomas are a group of eye disorders characterized by progressive optic nerve damage in which an important part is a relative increase in intraocular pressure (IOP) that can lead to irreversible... read more , or chronic constipation Constipation Constipation is difficult or infrequent passage of stool, hardness of stool, or a feeling of incomplete evacuation. (See also Constipation in Children.) No bodily function is more variable and... read more . All heterocyclics, particularly maprotiline and clomipramine, lower the threshold for seizures.

Monoamine Oxidase Inhibitors (MAOIs)

These drugs inhibit the oxidative deamination of the 3 classes of biogenic amines (norepinephrine, dopamine, 5-HT) and other phenylethylamines.

Their primary value is for treating refractory or atypical depression when selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and sometimes even electroconvulsive therapy Electroconvulsive therapy (ECT) Depressive disorders are characterized by sadness severe enough or persistent enough to interfere with function and often by decreased interest or pleasure in activities. Exact cause is unknown... read more (ECT) are ineffective.

Monoamine oxidase inhibitors (MAOIs) marketed as antidepressants in the US (eg, phenelzine, tranylcypromine, isocarboxazid) are irreversible and nonselective (inhibiting MAO-A and MAO-B). Another MAOI (selegiline), which inhibits only MAO-B at lower doses, is available as a patch.

Hypertensive crises can occur if MAOIs that inhibit MAO-A and MAO-B are ingested concurrently with a sympathomimetic drug or food containing tyramine or dopamine. This effect is called the cheese reaction because mature cheese has a high tyramine content. MAOIs are used infrequently because of concern about this reaction. The lower dosage of the selegiline patch is considered safe to use without specific dietary restrictions, unless the dosage must be higher than starting levels (a 6-mg patch). More selective and reversible MAOIs (eg, moclobemide, befloxatone), which inhibit MAO-A, are relatively free of these interactions but are not available in the US.

To prevent hypertension and febrile crises, patients taking MAOIs should avoid sympathomimetic drugs (eg, pseudoephedrine), dextromethorphan, reserpine, and meperidine as well as malted beers, Chianti wines, sherry, liqueurs, and overripe or aged foods that contain tyramine or dopamine (eg, fava or broad beans, yeast extracts, canned figs, raisins, yogurt, cheese, sour cream, soy sauce, pickled herring, caviar, liver, banana peel, extensively tenderized meats). Patients can carry 25-mg tablets of chlorpromazine and, as soon as signs of such a hypertensive reaction occur, take 1 or 2 tablets as they head to the nearest emergency department.

Common adverse effects of MAOIs include erectile dysfunction (least common with tranylcypromine), anxiety, nausea, dizziness, insomnia, pedal edema, and weight gain.

MAOIs should not be used with other classes of antidepressants, and at least 2 weeks (5 weeks with fluoxetine, which has a long half-life) should elapse between use of the 2 classes of drugs. MAOIs used with antidepressants that affect the 5-HT system (eg, SSRIs) may cause serotonin syndrome Serotonin Syndrome Serotonin syndrome is a potentially life-threatening condition resulting from increased central nervous system serotonergic activity that is usually drug related. Symptoms may include mental... read more (a potentially life-threatening condition whereby patients may exhibit mental status changes, hyperthermia, and autonomic and neuromuscular hyperactivity).

Patients who are taking MAOIs and who also need anti-asthmatic or anti-allergy drugs, a local anesthetic, or a general anesthetic should be treated by a psychiatrist plus an internist, a dentist, or an anesthesiologist with expertise in neuropsychopharmacology.

Melatonergic Antidepressant

Agomelatine is a melatonergic (MT1/MT2) agonist and a 5-HT2C receptor antagonist. It is used for major depressive episodes.

Agomelatine has fewer adverse effects than most antidepressants and does not cause daytime sedation, insomnia, weight gain, or sexual dysfunction. It is not addictive and does not cause withdrawal symptoms. It may cause headache, nausea, and diarrhea. It may also increase liver enzyme levels, and these levels should be measured before therapy is started and every 6 weeks thereafter. It is contraindicated in patients with hepatic dysfunction.

Agomelatine is taken at bedtime at a dose of 25 mg.

Ketamine-like Drugs

Numerous studies have shown that subanesthetic, rather than anesthetic, doses of ketamine often produce a uniquely rapid, though typically short-lived, resolution of depressive symptoms in patients with treatment-resistant major depressive disorder. The Food and Drug Administration (FDA) recently awarded an indication for the use of esketamine, the s-enantiomer of ketamine, in this population.

The presumed mechanism of action of subanesthetic ketamine is of particular interest because it does not primarily involve action at monoamine receptors as is the case with nearly all other currently approved antidepressants. Instead, effects are thought to begin with the blockade of the N-methyl-D-aspartic acid (NMDA) receptor that disinhibits glutamate release. This, in turn, increases brain-derived neurotrophic factor (BDNF) synthesis, and through the activation of both mammalian target of rapamycine (mTOR) and alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptors, leads to rapid increases in dendritic spine density in the cortical pyramidal cells specifically affected by chronic stress and hypercortisolemia.

The majority of patients given an antidepressant dose of ketamine experience a global improvement in depressive symptoms that peaks in 3 to 4 hours and then, in most cases, wanes over the next 1 to 2 weeks. Multiple administrations over several weeks lengthen the duration of improvement, but relapse rates are high over the ensuing months. Many ketamine clinics titrate the interval between treatments, and some patients can maintain improvement with only monthly treatments

Adverse effects are generally limited to a period of one to 2 hours following administration and include derealization Depersonalization/Derealization Disorder Depersonalization/derealization disorder is a type of dissociative disorder that consists of persistent or recurrent feelings of being detached (dissociated) from one’s body or mental processes... read more , increases in blood pressure, nausea, and vomiting. Because ketamine has a well-known abuse potential, administration should be confined to the office or hospital setting.

The starting dose is 0.5 mg/kg for IV ketamine or 56 mg for intranasal esketamine. There is no evidence of increased effectiveness for doses above 0.5 mg/kg for IV ketamine. The therapeutic range for intranasal esketamine is 56 to 84 mg.

The patient should be monitored in the clinic for 2 hours after administration and be advised not to drive until the following day. Acutely increased blood pressure may require intervention.

Drug Choice and Administration of Antidepressants

Choice of drug may be guided by past response to a specific antidepressant. Otherwise, selective serotonin reuptake inhibitors (SSRIs) are often the initial drugs of choice. Although the different SSRIs are equally effective for typical cases, certain properties of the drugs make them more or less appropriate for certain patients (see table Antidepressants ).

Table
icon

If one SSRI is ineffective, another SSRI can be substituted, or an antidepressant from a different class may be used instead. Tranylcypromine 20 to 30 mg orally twice a day is often effective for depression refractory to sequential trials of other antidepressants; it should be given by a physician experienced in use of monoamine oxidase inhibitors (MAOIs). Psychologic support of patients and loved ones is particularly important in refractory cases.

Insomnia, a common adverse effect of SSRIs, is treated by reducing the dose, giving the dose in the morning, or adding a low dose of trazodone or another sedating antidepressant at bedtime. Initial nausea and loose stools usually resolve, but throbbing headaches do not always go away, necessitating a change in drug class. An SSRI should be stopped if it causes agitation. When decreased libido, impotence, or anorgasmia occur during SSRI therapy, dose reduction or a change to a serotonin modulator or a norepinephrine-dopamine reuptake inhibitor may help.

SSRIs, which tend to stimulate many depressed patients, should be given in the morning. Giving the entire heterocyclic antidepressant dose at bedtime usually makes sedatives unnecessary, minimizes adverse effects during the day, and improves adherence. MAOIs are usually given in the morning and early afternoon to avoid excessive stimulation.

Therapeutic response with most classes of antidepressants usually occurs in about 2 to 3 weeks (sometimes as early as 4 days or as late as 8 weeks). For a first episode of mild or moderate depression, the antidepressant should be given for 6 months, then tapered gradually over 2 months. If the episode is severe or is a recurrence or if there is suicidal risk, the dose that produces full remission should be continued as maintenance.

For psychotic depression, the combination of an antidepressant and an antipsychotic Treatment Schizophrenia is characterized by psychosis (loss of contact with reality), hallucinations (false perceptions), delusions (false beliefs), disorganized speech and behavior, flattened affect... read more is more effective than either used alone. Patients who have recovered from psychotic depression are at higher risk of relapse than those who had nonpsychotic depression, so prophylactic treatment is particularly important.

Continued therapy with an antidepressant for 6 to 12 months (up to 2 years in patients > 50) is usually needed to prevent relapse.

Most antidepressants, especially SSRIs, should be tapered off (by decreasing the dose by about 25%/week) rather than stopped abruptly; stopping SSRIs abruptly may result in discontinuation syndrome (nausea, chills, muscle aches, dizziness, anxiety, irritability, insomnia, fatigue). The likelihood and severity of withdrawal varies inversely with the half-life of the SSRI.

Drugs Mentioned In This Article

Drug Name Select Trade
DELSYM
PARNATE
AFRINOL, SUDAFED
FETZIMA
No US brand name
PRISTIQ
VIVACTIL
MARPLAN
TEGRETOL
AVENTYL
ANAFRANIL
Vortioxetine
ELIXOPHYLLIN
LEXAPRO
Trimipramine
NORPRAMIN
INDERAL
LUVOX
EFFEXOR XR
REMERON
ADDERALL XR 10
PAXIL
ZOLOFT
ELDEPRYL
Vilazodone
NARDIL
CELEXA
PROZAC, SARAFEM
TOFRANIL
DEMEROL
LOPRESSOR, TOPROL-XL
CYMBALTA
Esketamine
OLEPTRO
WELLBUTRIN, ZYBAN
CLOZARIL
KETALAR
COUMADIN
ZONALON
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