Pharmacology: Antidepressants

Which SSRIs inhibit CYP2D6?

*Fluoxetine and paroxetine* are potent inhibitors of CYP2D6, which is responsible for the elimination of TCAs, neuroleptic drugs, and some antiarrhythmic and β-blockers.

Which SSRI has the highest number of drug interactions?

*Fluvoxamine* is an inhibitor of CYP1A2, CYP2C19 and CYP3A4 and therefore it also has high potential for drug interactions.

What is the cause of TCA-induced arrhythmia?

*TCAs inhibit cardiac fast sodium channels*, resulting in arrhythmia and possibly death (very common with TCA intoxication). Inhibition of sodium channels *prolongs phase-zero myocardial depolarization*, resulting in decreased conduction with a *prolonged QRS complex and negative inotropic effects*.

Generally, how do all antidepressants work?

All currently available antidepressant drugs *enhance monoamine neurotransmission* by one of several mechanisms. The most common mechanism is the inhibition of the serotonin transporter (SERT), the norepinephrine transporter (NET), or both.

Which SSRI undergoes extensive first-pass metabolism?

All of the SSRIs are well absorbed after oral administration, but *only sertraline* undergoes significant first-pass metabolism.

What is the typical regimen for treating depression?

An SSRI is the initial treatment of choice for most patients with depression and anxiety disorders. Their popularity comes from their ease of use, tolerability, and safety in overdose. Fluoxetine would be a reasonable first choice for adults or children not taking other drugs that may interact with it.

Which antidepressants are useful in treating anxiety disorders?

An antidepressant, usually an SSRI, is the drug of first choice. SSRIs can be used to treat generalized anxiety disorder, social anxiety disorder, posttraumatic stress disorder (PTSD), panic disorder and obsessive-compulsive disorder (OCD).

What are the signs of MAO inhibitor overdose, and how can it be managed?

An overdose can produce autonomic instability, hyperadrenergic symptoms, psychotic symptoms, confusion, delirium, fever, and seizures. It should be managed with cardiac monitoring, vital support and gastric lavage.

Which antidepressant is helpful in treating bulimia?

Antidepressants appear to be helpful in the treatment of bulimia, but not anorexia. Fluoxetine is approved for treatment of bulimia.

Can SSRIs cause serotonin syndrome when used with MAO inhibitors?

Are you really asking me this? Yes. Yes it can.

Why is the bioavailability of TCAs low?

As a result of variable first pass metabolism in the liver, TCAs have low and inconsistent bioavailability. Therefore, the patient's response is used to adjust dosage.

Which atypical anti-psychotics may be useful adjuncts in treating major depression?

Augmentation with an atypical antipsychotic agent may be helpful when the response to antidepressant agents is inadequate. *Quetiapine, aripiprazole and olanzapine* have been approved for adjunctive treatment of major depressive disorder.

What is bupropion?

Bupropion and its major metabolite hydroxybupropion are moderate inhibitors of norepinephrine and dopamine uptake (NDRIs). Bupropion also increases norepinephrine and dopamine release.

What is bupropion used for?

Bupropion assists in decreasing the craving and attenuating the withdrawal symptoms for nicotine in tobacco users.

What happens with bupropion overdose?

Bupropion is associated with seizures in overdose; it is contraindicated in patients with seizure disorder.

Which antidepressant is terrible in treating anxiety?

Bupropion is less effective than other antidepressants for treatment of anxiety.

Why doesn't bupropion cause sexual dysfunction?

Bupropion is not associated to sexual dysfunction problems which occur with SSRIs because it lacks the serotonergic component.

Which antidepressant is used to quit smoking?

Bupropion was approved in 1997 as a treatment for smoking cessation. Bupropion appears to be as effective as nicotine patches in smoking cessation.

If someone with depression is taking medications that interact with fluoxetine, what is the alternative to treatment?

Citalopram or sertraline would be a reasonable first choice for adults taking other drugs that could interact with fluoxetine.

Which SSRIs have low potential for adverse drug interactions?

Citalopram, escitalopram and sertraline have low potential for interactions.

Which TCAs tend to block SERT with higher affinity? Which prefer NET?

Clomipramine has very little affinity for NET but potently binds and blocks SERT. On the other hand, desipramine and nortriptyline are more selective for NET.

What is duloxetine?

Duloxetine inhibits serotonin and norepinephrine reuptake at all doses. It's extensively metabolized in the liver to numerous metabolites and should not be administered to patients with hepatic insufficiency. Adverse effects include nausea, dry mouth, constipation, decreased appetite, fatigue, somnolence, sweating, asthenia, dizziness, and sexual dysfunction.

How are SSRIs metabolized and excreted?

Excretion of the SSRIs is primarily through the kidneys, except for paroxetine and sertraline, which also undergo fecal excretion (35 and 50 %). Dosages of all of these drugs should be adjusted downward in patients with hepatic impairment.

Which kind of MAO inhibitor is better in treating major depression?

Experimentally, selective MAO-A inhibitors are thought to be more effective in treating major depression than type B inhibitors.

How does fluoxetine differ from the other SSRIs?

First, it has a much longer half-life (50 hours). Second, the metabolite of the S-enantiomer, S-norfluoxetine, is as potent as the parent compound. The half-life of the metabolite is quite long, averaging 10 days.

Which SSRI is approved for use in children and adolescents?

Fluoxetine is the only SSRI FDA-approved for treatment of major depressive disorder in children and adolescents.

How is IP3 broken down?

Gq protein-linked receptors activate PLC, which cleaves PIP2 into DAG and IP3. IP3 signaling is terminated by conversion to IP2 and then into IP1 by inositol polyphosphatase. IP1 is then converted to free inositol by inositol monophosphatase.

Which MAO inhibitors are non-selective and irreversible?

Isocarboxazid, phenelzine and tranylcypromine bind irreversibly and nonselectively to MAO-A and MAO-B.

Is lithium toxic?

Kinda, yeah. Lithium is clinically effective at a plasma concentration of 0.5 - 1mM; above 1.5 mM it produces a variety of toxic effects, so the therapeutic window is narrow.

What are the signs of SSRI overdose?

Large intakes of SSRIs do not usually cause cardiac arrhythmias (unlike TCAs), but *seizures are a possibility because all antidepressants may lower the seizure threshold*. The likelihood of fatalities from SSRI overdose is extremely low.

What is the mechanism of action for lithium?

Lithium *inhibits both inositol polyphosphatase and inositol monophosphatase*, thus blocking the regeneration of inositol. Free inositol is essential for the synthesis of PIP2, therefore lithium blocks the phosphatidylinositol signaling cascade in the brain. By blocking the regeneration of PIP2, lithium inhibits central adrenergic, muscarinic, and serotonergic neurotransmission. Inhibition by lithium is uncompetitive, therefore only neurons with active receptors will be affected by lithium. In those neurons, PIP2 levels will decrease, and PLC-coupled receptors will become inactive. This prevents actions of neurotransmitters responsible for mood swings. The hypothesis explains why lithium is brain-selective.

What form is lithium administered in?

Lithium is given by mouth as the carbonate salt, which is absorbed rapidly and completely from the gut. The drug is distributed throughout the body water and cleared by the kidneys with a half-life of ~20h. Plasma levels must be monitored.

What is the drug of choice for bipolar disorder?

Lithium is the standard treatment for bipolar disorder. It is used prophylactically in treating manic-depressive patients and in treatment of manic episodes.

What are the clinical uses of MAO inhibitors?

MAO inhibitors are now *rarely used* due to toxicity and potentially lethal food and drug interactions. Their primary use is in the *treatment of depression unresponsive to other antidepressants*.

How are MAO inhibitors administered?

MAO inhibitors are well absorbed orally but suffer high first-pass metabolism.

What is the mechanism of action for MAO inhibitors?

MAO inhibitors inactivate the enzyme, permitting neurotransmitter molecules to escape degradation and, therefore, to both accumulate within the presynaptic neuron and leak into the synaptic space. This is believed to cause activation of norepinephrine and serotonin receptors, and it may be responsible for the indirect antidepressant action of these drugs.

What is mirtazapine?

Mirtazapine is a *potent antagonist of central presynaptic α2-adrenergic receptors*, and thus enhances release of norepinephrine and 5-HT. Additionally, it is an antagonist at 5-HT2 and 5-HT3 receptors. Mirtazapine is also a potent H1 antagonist, which is associated with sedation and weight gain. It may be useful when insomnia or agitation is prominent.

How can serotonin syndrome be avoided with MAO inhibitors?

Most serotonergic antidepressants should be discontinued at least 2 weeks before starting a MAO inhibitor. Fluoxetine, because of its long half-life, should be discontinued 4-5 weeks before a MAO inhibitor is started. MAO inhibitors must be discontinued for at least 2 weeks before starting a serotonergic agent.

What is nefazodone?

Nefazodone is a weak inhibitor of SERT and NET and a potent antagonist of postsynaptic 5-HT2A. Nefazodone has been associated with hepatotoxicity and is no longer commonly prescribed.

Do MAO inhibitors have immediate antidepressant effects?

No. Although MAO is fully inhibited after several days of treatment, the antidepressant action of the MAO inhibitors is delayed several weeks.

Do TCAs and SSRIs have similar adverse effects?

No. SSRIs have little blocking activity at muscarinic, α-adrenergic, and histaminic H1 receptors. Therefore, common side effects associated with TCAs, such as orthostatic hypotension, sedation, dry mouth, and blurred vision, are not commonly seen with the SSRIs.

How are atypical anti-psychotics used to treat bipolar disorder?

Olanzapine and aripiprazole are approved for maintenance of bipolar disorder; quetiapine, risperidone, and ziprasidone are approved for treatment of acute mania or mixed episodes.

How is tyramine-induced hypertension treated?

Phentolamine or prazosin are helpful in the management of tyramine-induced hypertension.

What are the adverse effects of MAO inhibitors?

Possible adverse effects of treatment with MAO inhibitors include drowsiness, orthostatic hypotension, blurred vision, dry mouth, dysuria, and constipation.

Which antidepressant is best for premenstrual dysmorphic disorder?

SSRIs are beneficial to many women with PMDD. Fluoxetine and sertraline are approved for this indication.

Which antidepressants are the drugs of choice in treating depression?

SSRIs are the drugs of choice in treating depression.

Which MAO inhibitors may produce insomnia or agitation?

Selegiline and tranylcypromine have an amphetamine-like stimulant effects that may produce agitation or insomnia.

What happens with high doses of selegiline?

Selegiline has also antidepressant effects, particularly at high doses that also inhibit MAO-A or yield amphetamine-like metabolites. Selegiline is the first antidepressant available in a transdermal delivery system.

Which drugs may cause serotonin syndrome when given with MAO inhibitors?

Serotonergic agents such as SSRIs, SNRIs, TCAs or meperidine may result in a life-threatening serotonin syndrome when given with MAOi.

You patient is taking MAO inhibitors when they develop a common cold. Which drugs should you advise against giving to your patient?

Sympathomimetic drugs may also cause significant hypertension when combined with MAO inhibitors. Thus, OTC cold preparations that contain *pseudoephedrine and phenylpropanolamine are contraindicated* in patients taking MAO inhibitors.

How are TCAs metabolized?

TCAs are metabolized by the hepatic microsomal system and conjugated with glucuronic acid; ultimately, TCAs are excreted as inactive metabolites via the kidney.

Which antidepressants are useful in treating chronic pain?

TCAs are used in the treatment of neuropathic and other pain conditions. Drugs that possess both norepinephrine and 5-HT reuptake blocking properties are often useful in treating pain disorders. The SNRI duloxetine was the first antidepressant to be given FDA approval for the treatment of pain associated with diabetic neuropathy and fibromyalgia. SSRIs are not effective for chronic pain.

How are TCAs given? Do they penetrate the CNS?

TCAs are well absorbed upon oral administration; they are lipophilic and therefore penetrate into the CNS; their lipophilicity also causes these drugs to have variable half-lives.

Which MAO inhibitor is approved to treat early Parkinson's disease?

The MAO-B inhibitor *selegiline* is approved for treatment of early Parkinson's disease.

What is the mechanism of action for SSRIs?

The SSRIs block the reuptake of serotonin, leading to increased concentrations of the neurotransmitter in the synaptic cleft and, ultimately, to greater postsynaptic neuronal activity.

What are the signs of TCA overdose?

The most common method used in suicide attempts, overdose on TCAs can induce lethal arrhythmias (ventricular tachycardia and fibrillation). Additionally, blood pressure changes and anticholinergic effects including altered mental status and seizures are sometimes seen in TCA overdoses.

What are the symptoms of serotonin syndrome?

The syndrome includes hyperthermia, muscle rigidity, myoclonus, and rapid changes in mental status and vital signs. It is caused by overstimulation of 5-HT1A and 5-HT2 receptors.

Is lithium safe for pregnancy?

The use of lithium during pregnancy may increase the incidence of congenital cardiac anomalies, making it Category D and contraindicated in nursing mothers.

What are the two kinds of MAO?

There are two isozymes of MAO: MAO-A and MAO-B. MAO-A preferentially deaminates norepinephrine, epinephrine and serotonin. Dopamine and tyramine are metabolized by both isozymes.

When are SNRIs used?

These agents may be effective in treating depression in patients in whom SSRIs are ineffective.

What is the mechanism of action for SNRIs?

These drugs block the reuptake of serotonin and norepinephrine but differ from the TCAs by their lack of receptor-blocking activity at H1, muscarinic and α1 receptors.

What are amoxapine and maprotiline?

These tetracyclic antidepressants resemble TCAs such as desipramine: both are potent NET inhibitors and less potent SERT inhibitors. They, like TCAs, possess anticholinergic properties. Amoxapine is also a moderate inhibitor of postsynaptic D2 receptors, giving it some antipsychotic properties.

What is the mechanism of action for TCAs?

They *block the uptake of norepinephrine and serotonin* by nerve terminals by competition for the binding site of the carrier protein; this causes increased monoamine concentration in the cleft. In addition to their effects on amine uptake, most TCAs also block α-adrenergic, muscarinic, histamine and 5-HT receptors.

What is trazodone?

Trazodone is a *weak but selective inhibitor of SERT that is metabolized into a potent 5-HT2 antagonist*. Trazodone also blocks α1 and H1 receptors, which causes sedation (excellent hypnotic). The most common use of trazodone in current practice is as an *unlabeled hypnotic*. Rare but troublesome priapism may occur.

How is TCA overdose treated?

Treatment includes cardiac monitoring, airway support and gastric lavage. Sodium bicarbonate has been useful in reversing conduction block.

How do MAO inhibitors interact with tyramine-containing foods?

Tyramine (in aged cheeses and meats, and red wines) is normally inactivated by MAO in the gut. Patients on MAO inhibitors are unable to degrade tyramine obtained from the diet; this causes release of stored catecholamines from nerve terminals, resulting in occipital headache, stiff neck, tachycardia, nausea, hypertension, cardiac arrhythmias, seizures, and possibly, stroke.

Which drugs are SNRIs?

Venlafaxine and duloxetine are the SNRIs. Adverse effects include nausea, somnolence, dizziness, anxiety, sexual disturbances, and hypertension.

What is venlafaxine?

Venlafaxine is a potent inhibitor of 5HT uptake and, at higher doses, an inhibitor of norepinephrine uptake. It also inhibits reuptake of dopamine very weakly. At lower therapeutic doses it behaves like an SSRI. It lacks α1, cholinergic, and H1 receptor blocking properties. Adverse effects include nausea, somnolence, dizziness, anxiety, sexual disturbances, and hypertension.

What are nefazodone and trazodone?

When 5-HT reuptake is blocked by SSRIs, all 5-HT receptors are stimulated. Stimulation of 5-HT1A receptors in the raphe nucleus may help depression, but 5-HT2 receptors in forebrain may cause agitation or anxiety, and stimulation of 5-HT2 receptors in spinal cord may cause sexual dysfunction. *The main action of both nefazodone and trazodone appears to be blockade of the 5-HT2A receptor*. Inhibition of this receptor is associated with substantial antianxiety, antipsychotic, and antidepressant effects.

Name the tricyclic antidepressants.

• Amitriptyline • Nortriptyline • Imipramine • Desipramine • Clomipramine

What are the adverse effects of TCAs?

• Anti-muscarinic symptoms • Cardiac overstimulation. • TCAs slow cardiac conduction (Class I antiarrhythmics) • Orthostatic hypotension and reflex tachycardia (α1) • Sedation and weight gain (H1 blockade) • Sexual effects are common (clomipramine)

Name the selective serotonin re-uptake inhibitors.

• Citalopram • Escitalopram (S-enantiomer of citalopram) • Fluoxetine • Fluvoxamine • Paroxetine • Sertraline

What are the adverse effects of lithium?

• Confusion/motor impairment, followed by coma, and then convulsions and death • Tremor, sedation, ataxia, and aphasia. • Functional thyroid enlargement • *Reversible nephrogenic diabetes insipidus* • Edema • Acneiform skin eruptions. • Leukocytosis is always present

How do TCAs interact with other drugs?

• Elevations of TCA levels occur with CYP2D6 inhibitors • Caucasians have a CYP2D6 polymorphism (slow met.) • Worsening orthostatic hypotension with antihypertensives

What are the adverse effects of SSRIs?

• GI upset, diarrhea and other GI symptoms • Diminished sexual function and interest • Increase in headaches and insomnia or hypersomnia. • Some patients gain weight with paroxetine.

Name the MAO inhibitors.

• Isocarboxazid (hydrazine derivative) • Phenelzine (hydrazine derivative) • Tranylcypromine (non-hydrazine derivative) • Selegiline (non-hydrazine derivative)

Which drugs are not recommended for pregnant patients with bipolar disorder?

• Lithium (congenital cardiac abnormalities) • Valproate (neural tube defects) • Carbamazepine (risk of major malformations including neural tube defects, low birth weight, and fetal and neonatal vitamin K deficiency)

What precautions should be taken with TCAs?

• Narrow therapeutic index • Depressed patients who are suicidal should be given only limited quantities of these drugs and be monitored closely.

How do nefazodone and trazodone affect other drugs?

• Nefazodone is an inhibitor of CYP3A4. • Trazodone is metabolized by CYP3A4 (no inhibition)

Which psychiatric disorders may be helped with SSRIs?

• Obsessive-compulsive disorder • Panic disorder • Generalized anxiety disorder • Post-traumatic stress disorder • Social anxiety disorder • Premenstrual dysphoric disorder • Bulimia nervosa.

What are the alternatives to lithium treatment for bipolar disorder?

• Valproate (monitor liver function) • Carbamazepine (monitor CBC) • Atypical anti-psychotics • Olanzapine with fluoxetine • Lamotrigine is approved for maintenance treatment