Drugs used for the treatment of depression include the following:
Selective serotonin reuptake inhibitors (SSRIs)
Serotonin/norepinephrine reuptake inhibitors (SNRIs)
Serotonin-Dopamine Activity Modulator (SDAMs)
Tricyclic antidepressants (TCAs)
Monoamine oxidase inhibitors (MAOIs)
St. John’s wort ( Hypericum perforatum)
All antidepressants on the market are potentially effective. Usually, 2-6 weeks at a therapeutic-dose level are needed to observe a clinical response. The choice of medication should be guided by anticipated safety and tolerability, which aid in compliance; physician familiarity, which aids in patient education and anticipation of adverse effects; and history of previous treatments. Often, treatment failures are caused not by clinical resistance but by medication noncompliance, inadequate duration of therapy, or inadequate dosing.
Antidepressants can have central and peripheral anticholinergic effects, as well as sedative effects, and can block the active reuptake of norepinephrine (NE), serotonin (5-HT), and dopamine. SSRIs are metabolized via the cytochrome P-450 system and may have drug interactions on that basis. The degree of enzyme inhibition varies among SSRIs. Effects on blood levels and bioavailability of coadministered drugs, as well as pharmacodynamic interactions, account for most clinically significant SSRI-drug interactions.
All available antidepressants appear to work via one or more of the following mechanisms  :
Presynaptic inhibition of uptake of 5-HT or NE
Antagonist activity at presynaptic inhibitory 5-HT or NE receptor sites, thereby enhancing neurotransmitter release
Antagonism of NE beta or serotonin 5-HT2 receptors
N-Methyl-D-aspartate (NMDA) receptor antagonism
Induction of brain-derived neurotrophic factor (BDNF)
Inhibition of monoamine oxidase, thereby reducing neurotransmitter breakdown
SSRIs are the initial antidepressants of choice for uncomplicated depression because of their minimal anticholinergic effects.
They have the advantage of ease of dosing and low toxicity in overdose. SSRIs are greatly preferred over the other classes of antidepressants for the treatment of children and adolescents, and these agents are also the first-line medications for late-onset depression, due to their superior tolerability and comparatively more benign safety profile.
The SSRIs are not thought to be as worrisome in patients with cardiac disease, as they do not appear to exert any effect on blood pressure, heart rate, cardiac conduction, or cardiac rhythm; however, dose-dependent QT prolongation has been reported with citalopram. Because of the risk for QT prolongation, citalopram is contraindicated in individuals with congenital long QT syndrome. [101, 102]
Because the adverse-effect profile of SSRIs is less prominent than other agents, improved compliance is promoted. Common adverse effects of SSRIs include gastrointestinal upset, sexual dysfunction, bleeding, emotional blunting, cognitive dysfunction, and changes in energy level (ie, fatigue, restlessness).
The US Food and Drug Administration issued a safety information update in December 2011 concluding that it is unclear whether the use of SSRIs during pregnancy causes persistent pulmonary hypertension in the newborn. The FDA currently recommends that health care professionals and patients weigh the small potential risk of persistent pulmonary hypertension against the substantial risks of untreated depression during pregnancy. 
Citalopram enhances serotonin activity as a result of selective reuptake inhibition at the presynaptic neuronal membrane. It has minimal effects on norepinephrine and dopamine.
Although it has FDA approval only for depression, citalopram is commonly prescribed for other psychiatric disorders, including obsessive-compulsive disorder, generalized anxiety disorder, panic disorder, and premenstrual dysphoric disorder.
The FDA advises that the dose of citalopram not exceed 40 mg/day because of the risk of potentially fatal QT prolongation. Furthermore, higher doses have not been shown to be more effective in treating depression. 
Escitalopram is an SSRI and S-enantiomer of citalopram used for the treatment of depression. The mechanism of action is thought to be potentiation of serotonergic activity in the central nervous system resulting from inhibition of CNS neuronal reuptake of serotonin. Escitalopram has little or no effect on norepinephrine and dopamine reuptake.
Onset of depression relief may occur after 1-2 wk, but individual responses vary, and a full effect may not be seen until 8-12 weeks.
Fluoxetine is a commonly used SSRI and was the first of the SSRIs to become available in the United States. It selectively inhibits presynaptic serotonin reuptake with minimal or no effect on reuptake of norepinephrine or dopamine. It is commonly prescribed for many indications that are not FDA approved, including fibromyalgia, posttraumatic stress disorder, Raynaud phenomenon, social anxiety disorder, and selective mutism.
Fluvoxamine enhances serotonin activity due to selective reuptake inhibition at the neuronal membrane. It does not significantly bind to alpha-adrenergic, histamine, or cholinergic receptors and thus has fewer side effects than tricyclic antidepressants. Fluvoxamine is a strong inhibitor of cytochrome P-450. Although fluvoxamine is FDA approved only for obsessive-compulsive disorder, it is commonly prescribed for other psychiatric disorders, including social anxiety disorder, posttraumatic stress disorder, pain disorder, and major depression.
Paroxetine is a potent selective inhibitor of neuronal serotonin reuptake and also has a weak effect on norepinephrine and dopamine neuronal reuptake. It has slight anticholinergic effects and may cause more weight gain than other SSRIs. Paroxetine is sometimes prescribed for indications that are not FDA approved, such as eating disorders and the relief of vasomotor symptoms of menopause.
Sertraline selectively inhibits presynaptic serotonin reuptake. It has very minimal effects on norepinephrine and dopamine neuronal uptake. Sertraline is sometimes prescribed for indications that are not FDA approved, such as eating disorders, generalized anxiety disorder, and panic disorder.
Vilazodone's mechanism of antidepressant effect is related to serotonergic activity in the CNS through selective inhibition of serotonin reuptake. This agent is also a partial agonist at serotonergic 5-HT1A receptors, although the contribution of this activity to the drug's antidepressant effect is unknown.
Vilazodone is indicated for major depressive disorder. The dose should be adjusted when this agent is given with moderate or strong CYP3A4 inhibitors.
Vortioxetine enhances serotonergic activity through 5-HT reuptake inhibition. It also modulates serotonin receptor activity through 5-HT1A receptor agonism and 5-HT3 receptor antagonism, although the contribution of these activities to the antidepressant effect is not fully understood. It is approved to treat major depressive disorder in adults.
SNRIs can be used as first-line agents, particularly in patients with significant fatigue or pain syndromes associated with the episode of depression. The SNRIs also have an important role as second-line agents in patients who have not responded to SSRIs. Safety, tolerability, and side-effect profiles are similar to those of the SSRIs, with the exception that venlafaxine and desvenlafaxine have been associated (rarely) with a sustained rise in blood pressure. Venlafaxine has been particularly associated with hyponatremia.
Desvenlafaxine is an SNRI that is indicated for the treatment of major depressive disorder.
Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine uptake, and antidepressant action is thought to be due to serotonergic and noradrenergic potentiation in the central nervous system.
Venlafaxine and its active metabolite inhibit neuronal serotonin and norepinephrine reuptake. They are weak inhibitors of dopamine reuptake. In addition, it causes beta-receptor down-regulation. Venlafaxine is sometimes prescribed for non–FDA-approved indications, such as obsessive-compulsive disorder, hot flashes, neuropathic pain, attention-deficit/hyperactivity disorder, and posttraumatic stress disorder.
Levomilnacipran is the active enantiomer milnacipran and should be administered once daily. It is a potent inhibitor of neuronal serotonin and norepinephrine reuptake, and inhibits norepinephrine uptake with approximately 3-fold higher potency in vitro than serotonin without directly affecting the uptake of dopamine or other neurotransmitters.
TCAs have a long record of efficacy in the treatment of depression and have the advantage of lower cost. They are used less commonly because of the need to titrate the dose to a therapeutic level and because of their considerable toxicity in overdose. TCAs are often prescribed for many other psychiatric disorders, such as generalized anxiety disorder and posttraumatic stress disorder. They are also used to treat chronic pain, such as neuropathy, and migraine headaches.
Amitriptyline inhibits the reuptake of norepinephrine and, more potently, serotonin at the presynaptic neuronal membrane, which increases concentration in the CNS. It has a high affinity for histamine H1 and muscarinic M1 receptors. Amitriptyline can cause weight gain, sedation, and anticholinergic side effects. It is often used for non–FDA-approved indications, such as chronic pain management, diabetic neuropathy, migraine prophylaxis, and posttraumatic stress disorder.
Desipramine inhibits the reuptake of serotonin and, more potently, norepinephrine at the presynaptic neuronal membrane. It is a commonly used TCA that is relatively less sedating and tends to have fewer anticholinergic and antihistaminic adverse effects than other TCAs. It is sometimes used for off-label indications such as peripheral neuropathy and attention-deficit/hyperactivity disorder.
Imipramine is one of the oldest agents available for the treatment of depression. It is demethylated in the liver to desipramine. Imipramine inhibits the reuptake of norepinephrine and, more potently, serotonin at the presynaptic neuronal membrane. It has a strong affinity for alpha-adrenergic, H1, and M1 receptors. Common side effects include orthostasis, sedation, weight gain, and anticholinergic effects. It is also used off-label in the treatment of panic disorder, posttraumatic stress disorder, and attention deficit/hyperactivity disorder.
Clomipramine potently inhibits the reuptake of serotonin at the presynaptic neuronal membrane. It has strong affinities to both H1 and M1 receptors, which results in sedation, weight gain, and anticholinergic side effects. Although clomipramine is FDA approved only for obsessive-compulsive disorder, it has also been prescribed for depression, panic attacks, and chronic pain.
Nortriptyline blocks the reuptake of serotonin and, more potently, norepinephrine at the presynaptic neuronal membrane. It has less affinity for H1 and M1 receptors and, thus, is better tolerated than other TCAs. Although nortriptyline is FDA approved only for depression, it has also been prescribed for chronic pain, myofascial pain, anxiety disorders, and attention-deficit/hyperactivity disorder. As with desipramine, there is a therapeutic window for nortriptyline
Protriptyline increases the synaptic concentration of norepinephrine in the CNS by inhibiting reuptake at the presynaptic neuronal membrane. It has less affinity for H1 and M1 receptors and, thus, is better tolerated than tertiary amine TCAs.
Doxepin increases the concentration of serotonin and norepinephrine in the CNS by inhibiting their reuptake at the presynaptic neuronal membrane. These effects are associated with a decrease in the symptoms of depression. It has the highest affinity for H1 receptors of all TCAs and, thus, is very sedating and can cause weight gain.
Trimipramine inhibits reuptake of norepinephrine and serotonin at the presynaptic neuron and elicits strong anticholinergic effects. It has a high affinity for the H1 receptor and is thus very sedating, but it is useful for gastroesophageal reflux.
Amoxapine inhibits reuptake of norepinephrine and, to a lesser extent, serotonin at the presynaptic neuron. It also blocks dopamine receptors, causing it to have antipsychotic activity, as well.
Antidepressants, MAO Inhibitors
Monoamine oxidase inhibitors were the first antidepressants discovered, in the early 1950s. They are widely effective in a broad range of affective and anxiety disorders. MAOIs irreversibly block monamine oxidase, which has 2 forms, including MOAa and MOAb. MAOa breaks down serotonin and norepinephrine. MOAb metabolizes phenylethylamine. Both forms break down dopamine.
MOAIs are not considered first-line treatment for depression because of the side effects, drug-drug interactions, and dietary restrictions. Common side effects include hypotension, dizziness, dry mouth, gastrointestinal upset, urinary hesitancy, headache and myoclonic jerks. Because of the risk of hypertensive crisis with drugs that specifically inhibit MAOa in the gastrointestinal tract, patients on these medications must follow a low-tyramine diet.
Selegiline inhibits MAOb at lower doses and both forms at higher doses. Because it does not inhibit MAOa, it does not require dietary restrictions at lower doses. Lower doses of oral selegiline (Eldepryl) appear to lack antidepressant properties and are usually prescribed to treat Parkinson disease. Higher doses are used to treat major depressive disorder, and the selegiline transdermal patch is FDA approved for this indication. Selegiline is sometimes used off-label to treat attention-deficit/hyperactivity disorder.
Dietary restrictions are not required for the 6 mg/24 hour patch because there is no risk of hypertensive crisis with this dose, given the lack of MAOa inhibition. Higher doses require dietary restrictions. The patch may be beneficial to those that cannot take oral medications. To avoid serotonin syndrome, initiating and stopping selegiline must be handled carefully.
Tranylcypromine is used to treat major depression. It binds irreversibly to MAOa and to a lesser extent to MAOb, thereby reducing monoamine breakdown and enhancing synaptic availability. Clinical effects are not normally seen for 2-4 weeks. It has similar side effects as other MAOIs, but it is more likely to cause insomnia.
Phenelzine is used to treat depression. It irreversibly inhibits both MOAa and MOAb. Side effects are similar to those of other MAOIs, but anticholinergic side effects are more common. Phenelzine causes less insomnia than tranylcypromine but is more likely to cause sedation, weight gain, and sexual dysfunction.
Isocarboxazid is a nonselective hydrazine MAOI that is indicated for the treatment of depression. The mechanism by which MAOIs act as an antidepressant is not fully understood, but it is thought to be that these drugs increase the CNS concentrations of norepinephrine, dopamine, and serotonin.
Augmentation is a common strategy for treatment-resistant depression. It consists of adding a medication with a different mechanism of action to the therapeutic regimen.
Lithium carbonate can be used as an effective augmenting agent in combination with an antidepressant in cases of treatment-resistant depression. It can also be used to treat or prevent episodes of depression. Lithium is contraindicated in patients with significant renal impairment.
It is important to note that lithium interacts with many drugs. Use of lithium often requires monitoring of lithium levels and renal and thyroid function tests.
Buspirone is marketed as an antianxiety medication; however, it may have antidepressant effects at doses above 45 mg/day. The antidepressant effects may increase when buspirone is used in combination with SSRIs and TCAs in patients with treatment-resistant depression. Buspirone is a partial 5-HT1A agonist with serotonergic and some dopaminergic effects in the CNS. It has anxiolytic effects but may take up to 2-3 weeks for full efficacy.
Serotonin-Dopamine Activity Modulators
Serotonin-dopamine activity modulators (SDAMs) act as a partial agonist at 5-HT1A and dopamine D2 receptors at similar potency, and as an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors. This mechanism of action is unique from other atypical antipsychotic drugs.
Serotonin-dopamine activity modulator (SDAM) indicated as an adjunct treatment for major depressive disorder. Dosage modifications are necessary with renal or hepatic impairment. Dosage modifications are also needed for individuals who are poor metabolizers of CYP2D6, or if coadministered drugs alter metabolism by CYP2D6 or CYP3A4.
Serotonin-dopamine activity modulator (SDAM) indicated as an adjunct treatment for major depressive disorder. Dosage modifications are also needed for individuals who are poor metabolizers of CYP2D6, or if coadministered drugs alter metabolism by CYP2D6 or CYP3A4. No dosage adjustment is required for renal or hepatic impairment.
Atypical antidepressants include bupropion (Wellbutrin, Wellbutrin SR), mirtazapine (Remeron), and trazodone (Desyrel). These agents are effective in treating major depression and may be effective in combination therapy in major depressive disorder. This group also shows low toxicity in overdose. Wellbutrin SR may have an advantage over the SSRIs by causing less sexual dysfunction and weight gain.
Bupropion inhibits neuronal dopamine reuptake and decreases the rate of norepinephrine activity. In addition to major depressive disorder, the indications for bupropion include smoking cessation. Off-label indications include attention-deficit/hyperactivity disorder and depression associated with bipolar disorder. Common side effects include headache and mild weight loss. Unlike other antidepressants, bupropion does not cause sexual dysfunction.
Mirtazapine blocks both presynaptic and postsynaptic alpha-2 receptors but has low affinity for alpha-1 receptors. It also blocks serotonin receptors 5HT2 and 5HT3. Common side effects include sedation, weight gain, and dry mouth.
Trazodone is effective in the treatment of major depression. It inhibits reuptake of serotonin and modulates serotonergic neurotransmission. It also significantly blocks histamine (H1) receptors. Its most common side effect is sedation, and thus, it has an off-label indication as a hypnotic. It can be very rarely associated with priapism, a medical emergency and a dangerous side effect of this drug in men. It is often used at a low dosage (25 to 50 mg) as an adjunct to SSRIs to treat insomnia.
The CNS stimulants dextroamphetamine (Dexedrine) and methylphenidate (Ritalin) are sometimes used to augment antidepressants in patients with resistant depression.
This is an augmenting agent in resistant depression. It has been studied most for treating patients who are medically ill and depressed. It is available as a sustained-release preparation.
Methylphenidate has been mostly studied for treating patients who are medically ill and depressed. It is available as a sustained-release preparation.
Methylphenidate has been mostly studied for treating patients who are medically ill and depressed. It is available as a sustained-release preparation.
Thyroid hormones liothyronine (T3, Cytomel) may modulate the effect of antidepressants.
This synthetic salt of endogenous thyroid hormone may convert nonresponders (ie, nonresponders to antidepressants) to responders by increasing receptor sensitivity and enhancing the effects of TCAs.
Neurology & Psychiatry, Herbals
Although St. John's wort is considered a first-line antidepressant in many European countries, it has only recently gained popularity in the United States. Uses include treatment of mild to moderate depressive symptoms, but efficacy has not been demonstrated for major depression.
St John's wort is believed to act as an antidepressant by increasing concentrations of CNS neurotransmitters, including serotonin. The common dosage is 300 mg 3 times a day with meals to prevent GI upset. If no clinical response occurs after 3-6 months, encouraging the use of another medication is essential.
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- Physical Examination
- Major Depressive Disorder
- Depression with Anxious Distress
- Depression With Melancholic Features
- Depression With Catatonia
- Atypical Depression
- Postpartum Depression
- Seasonal Affective Disorder
- Major Depressive Disorder with Psychotic Features
- Other Specificed Depressive Disorders
- Metabolic Depression
- Cultural Influences on Expression of Depression
- Suicidal Ideation
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- Approach Considerations
- Pharmacologic Therapy for Depression
- Electroconvulsive Therapy
- Bright-Light Therapy
- Additional Therapies for Depression
- Treatment-Resistant Depression
- Pediatric Depression Treatment
- Depression During Pregnancy
- Postpartum Depression Treatment
- Diet and Activity
- Complications of Treatment for Depression
- Long-Term Monitoring
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