ANTIDEPRESSANTS

Depression

Are feelings of sadness and hopelessness, as well as the inability to experience pleasure in usual activities, changes in sleep patterns and appetite, loss of energy, and suicidal thoughts

Mania

Is characterized by the opposite behavior: enthusiasm, anger, rapid thought and speech patterns, extreme self-confidence, and impaired judgment. T

Serotonin
Norepinephrine
Dopamine

Antidepressants work by increasing the monoamines:
- The medications were developed based on the theory that depression results from imbalances or insufficiencies of these chemicals.
- Most antidepressants act to inhibit the reuptake of monoamines or inhibit their degradation by MAO.

Selective Serotonin Reuptake Inhibitor

- Are a group of antidepressant drugs that specifically inhibit serotonin reuptake, having 300- to 3000-fold greater selectivity for the serotonin transporter, as compared to the norepinephrine transporter.
- Have little blocking activity at muscarinic, α-adrenergic, and histaminic H1 receptors.
- Have largely replaced TCAs and monoamine oxidase inhibitors (MAOIs) as the drugs of choice in treating depression.

Fluoxetine
Citalopram
Escitalopram
Fluvoxamine
Paroxetine
Sertraline

Examples of Selective Serotonin Reuptake Inhibitor

Escitalopram

Is the pure S-enantiomer of citalopram.

- Obsessive–compulsive disorder (OCD)
- Panic disorder
- Generalized anxiety disorder (GAD)
- Post-traumatic stress disorder (PTSD)
- Social anxiety disorder
- Premenstrual dysphoric disorder (PMDD)
- Bulimia nervosa

SSRIs are also used for several other psychiatric disorders, including:

- Peak levels are seen in approximately 2 to 8 hours on average.
- Food has little effect on absorption (except with sertraline, for which food increases its absorption).
- The majority of SSRIs have plasma half-lives that range between 16 and 36 hours.
- Metabolism by cytochrome P450 (CYP450)–dependent enzymes and glucuronide or sulfate conjugation occur extensively.
- Fluoxetine differs from the other members of the class by having a much longer half-life (50 hours)

Pharmacokinetics of SSRI’s

Headache
Sweating
Anxiety
Agitation
Gastrointestinal (GI) Effects
Weakness and Fatigue
Sexual Dysfunction
Changes in Weight
Sleep Disturbances (insomnia and somnolence)

Although the SSRIs are considered to have fewer and less severe adverse effects than the TCAs and MAOIs, the SSRIs are not without adverse effects:

Paroxetine
Fluvoxamine

Are generally more sedating than activating, and they may be useful in patients who have difficulty sleeping.

Fluoxetine
Sertraline

They may be preferred for patients experiencing fatigue or excessive daytime sleepiness.

Bupropion
Mirtazapine

One option for managing SSRI-induced sexual dysfunction is to change the antidepressant to one with fewer sexual side effects, such as:

Fluoxetine
Sertraline
Fluvoxamine

Are approved for use in children to treat obsessive–compulsive disorder.

Fluoxetine
Escitalopram

Are approved to treat childhood depression.

Citalopram

Overdose with SSRIs does not usually cause cardiac arrhythmias, except? (which may cause QT prolongation)

True

TRUE OR FALSE
All of the SSRIs have the potential to cause a discontinuation syndrome after their abrupt withdrawal, particularly the agents with shorter half-lives and inactive metabolites.

Fluoxetine

Has the lowest risk of causing an SSRI discontinuation syndrome due to its longer half-life and active metabolite.

Venlafaxine
Desvenlafaxine
Levomilnacipran
Duloxetine

Examples of Serotonin/Norepinephrine Reuptake Inhibitors

Serotonin/Norepinephrine Reuptake Inhibitors

- Inhibit the reuptake of both serotonin and norepinephrine.
- These agents, may be effective in treating depression in patients in whom SSRIs are ineffective.
- Furthermore, depression is often accompanied by chronic painful symptoms, such as backache and muscle aches, against which SSRIs are also relatively ineffective.
- Have little activity at α-adrenergic, muscarinic, or histamine receptors and, thus, have fewer of these receptor-mediated adverse effects than the TCAs.
- May precipitate a discontinuation syndrome if treatment is abruptly stopped.

Diabetic Peripheral Neuropathy
Postherpetic Neuralgia
Fibromyalgia
Low Back Pain

Both SNRIs and the TCAs, with their dual inhibition of both serotonin and norepinephrine reuptake, are sometimes effective in relieving pain associated with:

Venlafaxine

- Is a potent inhibitor of serotonin reuptake and, at medium to higher doses, is an inhibitor of norepinephrine reuptake.
- Has minimal inhibition of the CYP450 isoenzymes and is a substrate of the CYP2D6 isoenzyme.
- Common side effects are nausea, headache, sexual dysfunction, dizziness, insomnia, sedation, and constipation.

Desvenlafaxine

Is the active, demethylated metabolite of venlafaxine.

Duloxetine

- Inhibits serotonin and norepinephrine reuptake at all doses.
- It is extensively metabolized in the liver to inactive metabolites and should be avoided in patients with liver dysfunction.
- GI side effects are common, including nausea, dry mouth, and constipation. Insomnia, dizziness, somnolence, sweating, and sexual dysfunction are also seen.
- May increase blood pressure or heart rate.
- Is a moderate inhibitor of CYP2D6 isoenzymes and may increase concentrations of drugs metabolized by this pathway, such as antipsychotics.

Levomilnacipran

- Is an enantiomer of milnacipran (an older SNRI used for the treatment of depression in Europe and fibromyalgia in the United States).
- The adverse effect profile is similar to other SNRIs.
- It is primarily metabolized by CYP3A4, and, thus, activity may be altered by inducers or inhibitors of this enzyme system.

Bupropion
Mirtazapine
Nefazodone
Trazodone
Vilazodone
Vortioxetine

Examples of Atypical Antidepressants

Bupropion

- Is a weak dopamine and norepinephrine reuptake inhibitor that is used to alleviate the symptoms of depression.
- Is also useful for decreasing cravings and attenuating withdrawal symptoms of nicotine in patients trying to quit smoking.
- May inhibit CYP2D6 and, thus, increase exposure to substrates of this isoenzyme.
- Should be avoided in patients at risk for seizures or those who have eating disorders such as bulimia.

Dry Mouth
Sweating
Nervousness
Tremor
Dose- dependent (increased risk for seizures)
Low Incidence of Sexual Dysfunction.

Side Effects of Bupropion

Mirtazapine

- Enhances serotonin and norepinephrine neurotransmission by serving as an antagonist at presynaptic α2 receptors.
- Additionally, some of the antidepressant activity may be related to antagonism at 5-HT2 receptors.
- It is sedating because of its potent antihistaminic activity, but it does not cause the antimuscarinic side effects of the TCAs, or interfere with sexual function like the SSRIs.
- Increased appetite and weight gain frequently occur
- Is markedly sedating, which may be an advantage in depressed patients having difficulty sleeping.

Nefazodone
Trazodone

- These drugs are weak inhibitors of serotonin reuptake. Their therapeutic benefit appears to be related to their ability to block postsynaptic 5-HT2a receptors.
- Both agents are sedating, probably because of their potent histamine H1 -blocking activity.
- Both agents also have mild to moderate α1 receptor antagonism, contributing to orthostasis and dizziness.

Trazodone

- Is commonly used off-label for the management of insomnia.
- Has been associated with priapism

Nefazodone

Has been associated with a risk for hepatotoxicity.

Vilazodone

- Is a serotonin reuptake inhibitor and a 5-HT1a partial agonist.
- Although the extent to which the 5-HT1a receptor activity contributes to its therapeutic effects is unknown, this possible mechanism of action renders it unique from that of the SSRIs.
- The adverse effect profile is similar to the SSRIs, including a risk for discontinuation syndrome if abruptly stopped.

Vortioxetine

- Utilizes a combination of serotonin reuptake inhibition, 5-HT1a agonism, and 5-HT3 and 5-HT7 antagonism as its suggested mechanisms of action to treat depression.
- It is unclear to what extent the activities other than inhibition of serotonin reuptake influence the overall effects of these drug.
- The common adverse effects include nausea, vomiting, and constipation, which may be expected due to its serotonergic mechanisms.

Tricyclic Antidepressants (TCA)

- Block norepinephrine and serotonin reuptake into the presynaptic neuron and, thus, if discovered today, might have been referred to as SNRIs, except for their differences in adverse effects relative to this newer class of antidepressants.
- Elevate mood, improve mental alertness, increase physical activity, and reduce morbid preoccupation in 50% to 70% of individuals with major depression.
- Are effective in treating moderate to severe depression. Some patients with panic disorder also respond to these drugs.

Imipramine
Amitriptyline
Clomipramine
Doxepin
Trimipramine

TRICYCLIC ANTIDEPRESSANTS
Tertiary Amines

Desipramine
Nortriptyline
Protriptyline

TRICYCLIC ANTIDEPRESSANTS
Secondary Amines (the N-demethylated metabolites of imipramine and amitriptyline, respectively)

Maprotiline
Amoxapine

TRICYCLIC ANTIDEPRESSANTS
Related Tetracyclic Antidepressants

Maprotiline
Desipramine

Are relatively selective inhibitors of norepinephrine reuptake.

Amoxapine

- Together with TCA these are potent inhibitors of the neuronal reuptake of norepinephrine and serotonin into presynaptic nerve terminals.
- Also blocks 5-HT2 and dopamine D2 receptors

Imipramine

- Has been used to control bed-wetting in children older than 6 years of age; however, it has largely been replaced by desmopressin and nonpharmacologic treatments (enuresis alarms).
- Is the most likely to cause orthostatic hypotension.

Amitriptyline

Have been used to help prevent migraine headache and treat chronic pain syndromes (for example, neuropathic pain) in a number of conditions for which the cause of pain is unclear.

Doxepin

Low doses of TCA’S, can be used to treat insomnia especially?

Weight Gain

Is a common adverse effect of the TCA’s.

Tricyclic Antidepressants

- Should be used with caution in patients with bipolar disorder, even during their depressed state, because antidepressants may cause a switch to manic behavior.
- Have a narrow therapeutic index (for example, five- to sixfold the maximal daily dose of imipramine can be lethal).
- Depressed patients who are suicidal should be given only limited quantities of these drugs and be monitored closely.
- May exacerbate certain medical conditions, such as benign prostatic hyperplasia, epilepsy, and preexisting arrhythmias.

Monoamine Oxidase Inhibitors

- Is a mitochondrial enzyme found in nerve and other tissues, such as the gut and liver.
- In the neuron, it functions as a “safety valve” to oxidatively deaminate and inactivate any excess neurotransmitters (for example, norepinephrine, dopamine, and serotonin) that may leak out of synaptic vesicles when the neuron is at rest.
- It may irreversibly or reversibly inactivate the enzyme, permitting neurotransmitters to escape degradation and, therefore, to accumulate within the presynaptic neuron and leak into the synaptic space.

Phenelzine
Tranylcypromine
Isocarboxazid
Selegiline

The four MAOIs currently available for treatment of depression include:

Phenelzine
Tranylcypromine
Isocarboxazid

Non-Selective (inhibit MAO-A + MAO-B)

Selegiline
Rasagiline

Selective (inhibit MAO-B)

Selegiline

Is also used for the treatment of Parkinson’s disease. It is the only antidepressant available in a transdermal delivery system.

Monoamine Oxidase Inhibitors (Phenelzine)

- Form stable complexes with the enzyme, causing irreversible inactivation.
- This results in increased stores of norepinephrine, serotonin, and dopamine within the neuron and subsequent diffusion of excess neurotransmitter into the synaptic space (Figure 10.9).
- These drugs inhibit not only MAO in the brain but also MAO in the liver and gut that catalyzes oxidative deamination of drugs and potentially toxic substances, such as tyramine, which is found in certain foods.

Selegiline
Tranylcypromine

Have an amphetamine-like stimulant effect that may produce agitation or insomnia.

Monoamine Oxidase Inhibitors

- Are indicated for depressed patients who are unresponsive or allergic to TCAs and SSRIs or who experience strong anxiety.
- A special subcategory of depression, called atypical depression, may respond preferentially to to these drugs.
- Because of their risk for drug– drug and drug–food interactions, these are considered last-line agents in many treatment settings.

Tyramine

- Contained in foods, such as aged cheeses and meats, chicken liver, pickled or smoked fish, and red wines, is normally inactivated by MAO in the gut.
- Causes the release of large amounts of stored catecholamines from nerve terminals, resulting in a hypertensive crisis, with signs and symptoms such as occipital headache, stiff neck, tachycardia, nausea, hypertension, cardiac arrhythmias, seizures,and, possibly, stroke.

Phentolamine
Prazosin

Helpful in the management of tyramine-induced hypertension.

True

TRUE OR FALSE
Due to the risk of serotonin syndrome, the use of MAOIs with other antidepressants is contraindicated. For example, SSRIs should not be co-administered with MAOIs. Both SSRIs and MAOIs require a washout period of at least 2 weeks before the other type is administered, with the exception of fluoxetine, which should be discontinued at least 6 weeks before a MAOI is initiated.

Lithium Salts

- Are used acutely and prophylactically for managing bipolar patients.
- Is effective in treating 60% to 80% of patients exhibiting mania and hypomania.
- Common adverse effects may include headache, dry mouth, polydipsia, polyuria, polyphagia, GI distress (give lithium with food), fine hand tremor, dizziness, fatigue, dermatologic reactions, and sedation.

Carbamazepine
Valproic Acid
Lamotrigine

Have been approved as mood stabilizers for bipolar disorder.

Chlorpromazine
Haloperidol

Other agents that may improve manic symptoms.
- Older

Risperidone
Olanzapine
Ziprasidone
Aripiprazole
Asenapine
Quetiapine

ATYPICAL ANTIPSYCHOTICS
- used for the management of mania

Quetiapine
Lurasidone
Combination of Olanzapine and Fluoxetine

Have been approved for bipolar depression.