Description
Linda is a 49-year-old female with a history of depression. She reports that she is suffering from fatigue, tearfulness, and difficulty sleeping. She has been taking fluoxetine 20mg for the past six months. What changes, if any, would you make to her plan of care and why?Prescriber’s GuideAntidepressants – https://online.vitalsource.com/reader/books/978110…Stahl’s Essential PsychopharmacologyChapter 7 – https://online.vitalsource.com/reader/books/978113…
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Antidepressants
Section 2 of 3
In the treatment of depression, symptoms reduction at 50 percent is considered a
response to treatment. The goal is complete remission of symptoms; however, this
can be difficult to reach at times and typically not reached with the first
antidepressant medication choice. Common causes of lack of remission include
sleep disturbances, tiredness, amotivation, anhedonia, and somatic complaints.
Adults are most likely to benefit from antidepressant use.
Click below to learn more about each class of antidepressants.
SSRIs
–
All SSRIs work by inhibiting the serotonin transporter. Most blockage occurs in the
midbrain rather than at the termination of the axons. Desensitization occurs first
at the presynaptic auto receptors. This causes a build up at the synapses, thus
causing postsynaptic serotonin receptors to desensitize as well. In large clinical
studies, there are minimal differences in effectiveness of different SSRIs. 5HT2C
antagonism is generally activating and helps to decrease fatigue, which can be
positive but also negative if the patient has extreme anxiety, agitation, or sleep
problems. Paroxetine, escitalopram, citalopram, and sertraline are all SSRIs.
SPARIs
–
Vilazodone is the medication in this class. SPARIs combine the action of SSRIs with
5HT1A partial agonism. This combination was previous achieved by adding on an
antipsychotic or buspirone to an SSRI or SNRI.
SNRIs
–
SNRIs combine SERT inhibition with different levels of norepinephrine transporter
inhibition. Thought to have two actions, SNRIs also affect dopamine in the
prefrontal cortex. Milnacipran is the most potent inhibitor of the norepinephrine
transporter. Venlafaxine is a commonly prescribed SNRI. The XR version helps to
decrease side effects and decreases the number of doses needed daily. Other
SNRIs include duloxetine and desvenlafaxine. This class can also be used for
chronic pain.
NDRIs
–
Bupropion is the only medication in this class. It is believed that this medication
blocks the reuptake of norepinephrine and dopamine. Three formulations are
available for immediate release, twice a day dosing (SR), and once a day dosing (XL).
This medication has been used for depression, ADHD, and smoking cessation.
MAOIs
–
MAOIs are considered classic antidepressants. This class cannot be mixed with
several other psychiatric medications. Because of this, they are not often used and
require a wash-out period between their use and use of other antidepressants.
Phenelzine, tranylcypromine, and isocarboxazid are all irreversible enzyme
inhibitors. This class of medication requires some dietary restrictions as
well. Foods that should be avoided when taking these medications include the
following: tap and unpasteurized beer, aged cheeses, banana peel, soy/tofu,
sauerkraut, kimchee, or dried, aged, smoked, fermented, spoiled or improperly
stored meat, poultry or fish. Selegiline is a selective MAO-B inhibitor at low oral
doses; administering low oral doses of selegiline does not have any dietary
restrictions but also does not inhibit MAO-A in the brain and is therefore not an
antidepressant. At high oral doses, selegiline does inhibit MAO-A and therefore has
antidepressant effects but requires the need to restrict dietary tyramine.
Tricyclics
–
Tricyclics are also considered classic antidepressants. This drug class blocks
serotonin and norepinephrine reuptake. Clomipramine has a greater affinity to
block serotonin while desipramine, maprotiline, nortriptyline, and protriptyline
block norepinephrine more. They all block both to some extent.
SARIs
–
The prototype drug that blocks serotonin 2A and 2C (5HT2A and 5HT2C)
receptors as well as serotonin reuptake is trazodone, classified as a serotonin
antagonist/reuptake inhibitor (SARI), or, more fully, as a serotonin 2A/2C
antagonist and serotonin reuptake inhibitor. Nefazodone is another SARI with
robust 5HT2A antagonist actions and weaker 5HT2C antagonist and SERT
inhibition but is no longer commonly used because of rare liver toxicity. Trazodone
dosing effects how this medication works. Trazodone is often used with other
SSRIs to help with insomnia.
L-5 Methyfolate can be used to augment antidepressants. It is believed that this form
of folate effects monoamine levels. Genetic variations can affect L-methylfolate level.
One can consider symptoms in the selection of antidepressants. Concentration and
fatigue is thought to be related to norepinephrine and dopamine. The medications
most effective for this are NDRIs, NRIs, SNRIs, MAOIs. Sleep disturbance may
benefit from sedating antidepressants like mirtazapine and trazodone. Pain with
depression may be best treated with SRNIs. Sexual dysfunction can be treated with
NDRI, SARIs, or MAOIs; stopping SNRIs or SSRIs may be helpful since they can
cause sexual dysfunction.
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Serotonin Reuptake Inhibitors and Similar Antidepressants – West Coast University APRN v2
Serotonin Reuptake Inhibitors and Similar
Antidepressants
Antidepressants encompass several drug classes and are used to treat individuals with depression, anxiety, and
psychiatric conditions, as well as those with chronic pain and symptoms of menopause. Antidepressants include selective
serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a
class of their own. Antidepressants are indicated as the 1st-line treatment for anxiety disorders and major depressive
disorder (MDD) and are contraindicated in cases of current or recent use of monoamine oxidase inhibitors. Therapeutic
response to antidepressants takes 2–4 weeks and complete benefit is not seen until up to 8 weeks, which is attributed to
downstream cellular responses necessary for eliciting a physiologic response. In general, serotonin-affecting
antidepressants are well tolerated, but caution must be taken while prescribing them in combination with other drugs that
inhibit or induce the same hepatic cytochrome P450 enzymes to prevent increased levels of both drugs. An overdose
can be life-threatening. It is important to recognize the signs and symptoms of SSRI/SNRI overdose to enable prompt
treatment in an emergency setting.
Last updated: July 28, 2023
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Serotonin Reuptake Inhibitors and Similar Antidepressants – West Coast University APRN v2
CONTENTS
Chemistry and
Pharmacodynamics
Pharmacokinetics
Classification and Indications
Adverse Effects and
Contraindications
Overdose
References
Chemistry and Pharmacodynamics
Mechanisms of action
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Serotonin Reuptake Inhibitors and Similar Antidepressants – West Coast University APRN v2
Selective serotonin reuptake inhibitors (SSRIs):
Vary considerably in their chemical structures
Have similar mechanisms of action, which result in increased synaptic serotonin
(also known as 5-hydroxytryptamine (5-HT))
Serotonin-norepinephrine reuptake inhibitors (SNRIs) have a similar mechanism of
action to SSRIs:
Chemical structures of duloxetine, milnacipran, and venlafaxine are dissimilar.
Desvenlafaxine and venlafaxine are bicyclic phenylethylamines with a similar
structure.
Duloxetine is a naphthalene derivative.
Serotonin antagonist and reuptake inhibitors (SARIs): trazodone and nefazodone
Inhibit reuptake of serotonin by blocking the 5-HT2A receptor (antagonist)
Induce significant changes in the 5-HT presynaptic receptor adrenoreceptors
Block histamine (H₁) and α-1 adrenergic receptors
5-HT1A receptor partial agonist: vilazodone
Inhibits CNS neuron serotonin uptake
No significant effect on the reuptake of norepinephrine (NE) or dopamine
Serotonin modulator and stimulator(SMS): vortioxetine
Inhibits serotonin reuptake
Has agonist activity at the 5-HT1A receptor and antagonist activity at the 5-HT3
receptor
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Antidepressant mechanisms: The basic mechanism of action for commonly prescribed antidepressant
medications are listed. These include MAO inhibitors, the alpha-2 antagonist mirtazapine, the SSRI
fluoxetine, the SARI trazodone, the TCA desipramine, and the tetracyclic drug maprotiline.
Image by Lecturio.
Pharmacodynamics
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SSRIs:
“Selective”: have affinity for the serotonin receptor and very little affinity for
other receptors
Many types of pre- and postsynaptic serotonin receptors exist (e.g., 5-HT2A and
5-HT2C).
SSRIs decrease the action of the presynaptic serotonin reuptake pump by 60%–
80% → increased 5-HT levels in the synaptic cleft
Increased levels of serotonin are not sufficient to treat depression. The
beneficial effect on mood takes several weeks and occurs due to:
Increased production of neuroprotective proteins
Treatment with an SSRI for weeks modifies the serotonergic receptors.
SNRIs:
Vary in their affinity for the serotonin and NE transporters → ↑ NE and 5-HT
levels in the synaptic cleft
The degree to which serotonin and NE reuptake is inhibited depends on the
dose and drug.
SARIs:
Relatively targeted at the 5-HT2A and 5-HT2C receptors
5-HT2A and 5-HT2C are G-protein-mediated receptors located in the neocortex
→ antidepressant action
Also block H₁ receptors
Physiologic effects:
Physical symptoms may improve in the 1st 1–2 weeks (energy, sleep, appetite).
Affective symptoms improve after physical symptoms (mood, concentration, selfesteem).
Pharmacokinetics
Secondary serotonin reuptake inhibitors
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Absorption:
Well-absorbed in the GI tract, not affected by food
Reach peak plasma levels in a few hours
Distribution:
Lipophilic
Widely distributed throughout the body (including the brain)
Metabolism:
Via cytochrome P450 (CYP)2D6, CYP3A4, and CYP2C19 pathways: significant
for drug interactions
Half-lives vary from 21 hours (paroxetine) to 5 days (fluoxetine after long-term
use).
Fluoxetine may be dosed every other day owing to its very long half-life.
All SSRIs except fluvoxamine produce pharmacologically active metabolites.
Fluoxetine is the only drug with an active metabolite that has antidepressant
activity.
Excreted in the urine and feces
Serotonin-norepinephrine reuptake inhibitors
Absorption:
Food decreases the rate but not the degree of absorption.
Taking with meals may reduce nausea, which is generally the most common side
effect of SNRIs.
Distribution:
Duloxetine is highly protein bound and primarily undergoes hepatic clearance.
Other SNRIs are not as highly protein bound as duloxetine. Renal excretion plays
a significant role in their clearance.
Metabolism:
Significant interindividual differences in the clearance of SNRIs
Doses may vary substantially among individuals.
Excretion:
Partially metabolized by the kidneys and excreted in the urine
Dosage adjustments may be required in individuals with CKD.
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Serotonin antagonist and reuptake inhibitor = trazodone
(nefazodone is not currently available in the US)
Short-acting drug with a half-life of 7 hours
Metabolized via the CYP3A4 pathway
Excreted in the urine
Serotonin modulator and stimulator = vortioxetine
Protein binding: 98%
Hepatic metabolism mainly via oxidation by CYP450 isoenzymes, primarily CYP2D6,
and subsequent glucuronic acid conjugation to an inactive carboxylic acid metabolite
Long elimination half-life: approximately 66 hours (causes fewer withdrawal symptoms
if doses are missed)
Excreted in the urine and feces
5-Hydroxytryptamine1A receptor partial agonist = vilazodone
Protein binding: approximately 96%–99%
Metabolism: extensively hepatic via CYP3A4 (major pathway) and CYP2C19 and
CYP2D6 (minor pathways)
Elimination half-life: approximately 25 hours
Classification and Indications
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Serotonin Reuptake Inhibitors and Similar Antidepressants – West Coast University APRN v2
Antidepressant medications that affect serotonin levels in the brain to treat
depression, anxiety, and other conditions are classified into several groups. The most
commonly prescribed antidepressants are SSRIs. Other important classes of
antidepressants include monoamine oxidase inhibitors (MAOIs),
tricyclic antidepressants (TCAs), and the NE/dopamine reuptake inhibitor (NDRI)
bupropion.
Classification
The brand names of commonly used medications are listed in parentheses for further
understanding.
SSRIs:
Citalopram (Celexa)
Escitalopram (Lexapro)
Fluoxetine (Prozac)
Fluvoxamine (Luvox)
Paroxetine (Paxil)
Sertraline (Zoloft)
SNRIs:
Duloxetine (Cymbalta)
Venlafaxine (Effexor)
Desvenlafaxine (Pristiq)
Milnacipran (Savella)
SARIs:
Trazodone (generic)
Nefazodone: not currently available in the US (August 2021), but may soon be
made available
SMS: vortioxetine (Trintellix)
Indications
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Antidepressants are used to treat several psychiatric conditions, and
SSRIs/SNRIs/SARIs/SMS are most commonly used to treat major depressive disorder
(MDD) such as unipolar depression and anxiety disorders, and also to treat
chronic pain.
General indications for antidepressant medications:
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MDD:
SSRIs are usually the preferred 1st-line agents (except fluvoxamine).
Concomitant therapy with psychosocial/behavioral therapy should be
considered.
Anxiety disorders:
Generalized anxiety disorder
Social anxiety disorder
Panic disorder
OCD: SSRIs and SNRIs are effective.
Chronic pain:
Neuropathic pain
Chronic musculoskeletal pain
Fibromyalgia:
Duloxetine
Milnacipran (Savella) indicated for fibromyalgia, not depression
Unique uses for some medications that may be preferred over other similar drugs:
Premature ejaculation: sertraline
Vasomotor symptoms of menopause: paroxetine, venlafaxine, escitalopram
Vulvodynia may respond to SNRIs.
Migraine prophylaxis in individuals without depression: escitalopram,
venlafaxine
PTSD: venlafaxine, paroxetine
Bulimia nervosa: fluoxetine
Premenstrual dysphoric disorder (PMDD): fluoxetine, sertraline
Insomnia: Trazodone is used more as a sleep aid than to treat depression.
Atomoxetine (Strattera) is used for ADHD and narcolepsy:
The exact mechanism of action is unknown; however, it selectively inhibits
NE reuptake.
Not used for depression
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Adverse Effects and Contraindications
None of the SSRIs significantly affect the α-adrenergic, histaminic, or cholinergic
receptors, except for paroxetine, which has a weak antagonistic effect on the
cholinergic receptors. The side effects of all SSRIs are due to their effects on the
serotonin receptors.
Adverse effects
SSRIs:
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Serotonin Reuptake Inhibitors and Similar Antidepressants – West Coast University APRN v2
GI:
Nausea
Diarrhea (most common with sertraline)
Xerostomia (dry mouth)
Diaphoresis
Sexual dysfunction:
Anorgasmia in women or delayed orgasm in men (sertraline may be used as a
treatment for premature ejaculation)
Decreased libido
Erectile dysfunction
Weight changes: also may be due to depression itself
Weight gain may be seen with paroxetine.
Weight loss may be seen with fluoxetine.
Neurologic:
Dizziness
Headache
CNS depression
Insomnia
Increased risk of bleeding due to inhibition of platelet serotonin uptake (and drug
interaction with clopidogrel)
Hypoglycemic effects (and drug interactions with sulfonylureas)
Hyponatremia
Cardiovascular: Citalopram may cause QT prolongation.
SNRIs, vilazodone, and vortioxetine:
Similar side effects as SSRIs
SNRIs may cause a slight increase in blood pressure.
Trazodone (SARI):
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GI:
Constipation
Nausea
Xerostomia (dry mouth)
Neurologic/psychiatric:
Dizziness
Headache
Sedation
Blurred vision
Discontinuation syndrome:
Occurs more often in individuals taking higher doses
Commonly observed in drugs with shorter half-lives
Least risk with fluoxetine
Greatest risk with paroxetine and venlafaxine
Risk can be reduced by slowly tapering over several weeks.
Abruptly stopping SSRIs or SNRIs may cause:
Dizziness
Fatigue
Headache
Nausea
Insomnia
Irritability
Paresthesias: including a feeling of “electric-like” shocks
Serotonin syndrome (a potentially life-threatening side effect):
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Usually caused by > 1 medication affecting the serotonin receptor
Was 1st described as a reaction between SSRIs and MAOIs
Drug combinations with SSRIs/SNRIs/other serotonergic antidepressants:
To treat migraine: triptans and ergots
Antidepressants: TCAs, MAOIs, antipsychotics
Anticonvulsants: carbamazepine, valproic acid
Antianxiety drug: buspirone
Opioid analgesics: tramadol, methadone, codeine
Over-the-counter cough medication: dextromethorphan
Herbal supplements for depression: St. John’s Wort, 5-HTP
Antibiotic: linezolid
Muscle relaxant: cyclobenzaprine
Street drugs: cocaine, methamphetamine
Symptoms include CNS stimulation, cardiovascular stimulation, and GI stimulation:
Severe muscle rigidity
Mydriasis
Myoclonus
Hyperreflexia
Hyperthermia
Seizures
Tachycardia
Unstable blood pressure
Diarrhea
Mnemonic to recall serotonin syndrome manifestations: “Madam’s tips”
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M = mental status changes
A = agitation
D = diarrhea
A = ataxia
M = myoclonus
S = shivering
T = tachycardia
I = increased reflexes
P = pyrexia
S = sweating
Drug interactions
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Both drug factors and patient factors can contribute to the toxicity of SSRIs/SNRIs in
some individuals.
Drug factors: Some SSRIs and SNRIs are moderate-to-potent inhibitors of
hepatic cytochrome P450 → drug-drug interactions by altering blood levels of
other medications that depend on these enzymes for clearance or activation
Patient factors: Enzyme may function differently in individuals with significant
variations in the CYP2D6 gene.
“Slow metabolizers”
“Extensive metabolizers”
CYPs are hepatic enzymes that metabolize several drugs:
Render the drug either more or less active
Combinations of drugs using the same metabolic pathway can cause serious
adverse effects.
Examples of the CYP450 family of proteins used by antidepressants:
CYP2D6
CYP3A4
CYP2C9
CYP1A2
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SSRI drug interactions with other drugs that are metabolized by CYP450 enzymes:
Citalopram and escitalopram inhibit liver enzymes much less than other SSRIs.
Fluoxetine and paroxetine are potent inhibitors of CYP2D6 causing ↑ 2D6
substrate levels
Other CYP2D6 inhibitors that can interact with SSRIs and should be used with
caution:
Antiarrhythmic agents: amiodarone, quinidine
H₂ histamine receptor antagonist: ranitidine
Bupropion (an antidepressant in its own class)
Cinacalcet (used for hyperparathyroidism)
Other CYP2D6 substrates (SSRIs can interact with other drugs and lead to
increased drug levels and adverse effects):
β-blockers:
Used for hypertension or cardiac conditions: propranolol, metoprolol,
atenolol, bisoprolol
Combination with SSRIs can ↑ drug levels and cause hypotension
Tamoxifen: used to treat breast cancer
Antinausea medications: ondansetron, metoclopramide
Other antidepressants:
Tricyclic (amitriptyline, imipramine, nortriptyline)
Combination with SSRIs can ↑ drug levels and lead to serotonin
syndrome
Antipsychotics:
Aripiprazole, haloperidol, olanzapine, quetiapine, risperidone
Combination with SSRIs can ↑ drug levels and lead to serotonin
syndrome
1st-generation antihistamines/H₁-receptor antagonists: chlorpheniramine,
diphenhydramine
Muscle relaxants: cyclobenzaprine
Pain medications/opioid analgesics: codeine or tramadol
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CYP3A4 substrates: SSRIs can interact with:
Some calcium channel blockers
Statins
Benzodiazepines
Hypnotics: zopiclone and zolpidem
Macrolide antibiotics: clarithromycin and azithromycin
Psychiatric medications: haloperidol, mirtazapine
Antivirals used in the management of HIV
CYP3A4 inhibitors and inducers: SSRIs can also interact with:
Antifungals: ketoconazole
Calcium channel blockers: specifically diltiazem and verapamil
Grapefruit juice
Antivirals used in the management of HIV (note that they are also CYP34
substrates, as listed above)
Anticonvulsants: carbamazepine, phenytoin, barbiturates
Rifampin
St. John’s wort
CYP2C9 pathway: fluoxetine can also interact with:
Antifungals: voriconazole
Some TCAs
Benzodiazepines
Proton pump inhibitors: omeprazole
Sulfonylureas: glipizide or glimepiride
Fluvoxamine (a different SSRI) is a potent CYP2C9 inhibitor:
↑ Levels of the antipsychotics clozapine, thioridazine, and olanzapine
Contraindicated with the hypnotic drug ramelteon (Rozerem), melatonin, and the
muscle relaxant tizanidine (Zanaflex) due to the risk of causing increased drug
levels and CNS depression
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SNRI drug interactions:
Duloxetine is a moderately potent inhibitor of CYP2D6 and may interact with
other drugs:
↑ Metoprolol levels
↑ Thioridazine levels and risk of QT prolongation
Other SNRIs (venlafaxine, desvenlafaxine, and milnacipran) do not have
significant effects on CYP enzymes.
SARI (trazodone) drug interactions:
Some sedatives or CNS depressants can cause increased sedation:
Opioids
Benzodiazepines
Barbiturates
Ethanol
Potent CYP2D6 inhibitors (paroxetine, tamsulosin): ↑ trazodone levels
5-HT1A receptor partial agonist (vilazodone) drug interactions:
Similar adverse effects and contraindications as with SSRIs
Drug interactions: potent CYP3A4 inhibitors ↑ vilazodone levels
Antibiotics: clarithromycin, azithromycin
Antifungals: itraconazole, ketoconazole
Antivirals: indinavir, nelfinavir, ritonavir, saquinavir used in the
management of HIV infection
Not all drugs within a class of medications inhibit CYP3A4.
Vortioxetine drug interactions: Use with other CYP2D6 inhibitors can ↑ vortioxetine
levels
Contraindications
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All SSRIs are contraindicated in individuals currently taking MAOIs to treat depression.
The combination may increase the risk of serotonin syndrome.
Additive risks of CNS depression and psychomotor impairment
SSRIs/SNRIs/SARIs/SMS are not recommended for individuals with bipolar depression
as these drugs may induce mania (except for fluoxetine).
SNRIs:
Contraindicated with MAOIs
Duloxetine is contraindicated in individuals with narrow-angle glaucoma.
Overdose
Generally, an overdose of SSRI/SNRI/similar drugs can cause signs and symptoms of
neuromuscular excitation and autonomic stimulation.
Signs:
Clonus
Agitation
Diaphoresis
Tremors
Hyperreflexia
Hyperthermia
Treatment:
Supportive care:
Discontinue serotonergic therapies.
Benzodiazepines may be needed for severe agitation.
Intubation may be required if there is a concern to protect the airway.
Cooling for individuals with hyperthermia
Individuals exhibiting refractory symptoms can be treated with cyproheptadine.
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Serotonin Reuptake Inhibitors and Similar Antidepressants – West Coast University APRN v2
Clinical characteristics of serotonin syndrome
Image by Lecturio.
References
1. O’Donnell, J.M., Bies, R.R., Shelton, R.C. (2018). Drug Therapy of Depression and Anxiety Disorders. In:
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