Antidepressant Agents

Depression
• Major depressive disorder (MDD) is characterized
by depressed mood most of the time for at least 2
weeks or loss of interest or pleasure in most
activities, or both.
• depression is characterized by disturbances in
sleep and appetite as well as deficits in cognition
and energy.
• Thoughts of guilt, worthlessness, and suicide are
common.
• Coronary artery disease, diabetes, and stroke
appear to be more common in depressed patients
 Uses of antidepressants
• panic disorder
• generalized anxiety disorder (GAD)
• post-traumatic stress disorder (PTSD)
• obsessive-compulsive disorder (OCD)
• to treat pain disorders such as neuropathic pain and the
pain associated with fibromyalgia.
• premenstrual dysphoric disorder (PMDD)
• mitigating the vasomotor symptoms of menopause
• treating stress urinary incontinence
• primary use remains the treatment for MDD.
Pathophysiology of Major Depression
• a deficit in function or amount of
monoamines (the monoamine hypothesis) is
central to the biology of depression
• neurotrophic factors (the neurotrophic
hypothesis)
• endocrine factors
 Neurotrophic Hypothesis
• depression is associated with the loss of
neurotrophic support and that effective
antidepressant therapies increase
neurogenesis and synaptic connectivity in
cortical areas such as the hippocampus.
• BDNF is thought to exert its influence on
neuronal survival and growth effects by
activating the tyrosine kinase receptor B in
both neurons and glia
• stress and pain are associated with a drop in BDNF
levels in CSF and serum
• loss of neurotrophic support contributes to atrophic
structural changes in the hippocampus and other
areas such as the medial frontal cortex and anterior
cingulate.
• The hippocampus is known to be important both in
contextual memory and regulation of the
hypothalamic-pituitary-adrenal (HPA) axis
• the anterior cingulate plays a role in the integration of
emotional stimuli and attention functions
• the medial orbital frontal cortex is also thought to
play a role in memory, learning, and emotion.
Monoamines & Other Neurotransmitters

• Depression is related to a deficiency in the amount

or function of cortical and limbic serotonin (5-HT),
norepinephrine (NE), and dopamine (DA)
• Genetics
• All classes of antidepressants appear to enhance the
synaptic availability of 5-HT, norepinephrine, or
dopamine.
• A number of studies of depressed patients have
found elevated glutamate content in the
cerebrospinal fluid of depressed patients
• Volumetric changes in the brain areas of
depressed patients in which glutamate
neurons and their connections are most
abundant, including the amygdala and
hippocampus.
• Stress is known to enhance the release of
glutamate in rodents, and antidepressants
inhibit stress-induced presynaptic release of
glutamate in these models
Neuroendocrine Factors in the Pathophysiology
of Depression
• MDD is associated with elevated cortisol levels
• Thyroid dysregulation has also been reported in depressed patients.
• These abnormalities include a blunting of response of thyrotropin
to thyrotropin-releasing hormone, and elevations in circulating
thyroxine during depressed states.
• Clinical hypothyroidism often presents with depressive symptoms,
which resolve with thyroid hormone supplementation.
• Estrogen deficiency states, which occur in the postpartum and
postmenopausal periods, play a role in the etiology of depression
in some women
• severe testosterone deficiency in men is sometimes associated with
depressive symptoms.
• Hormone replacement therapy in hypogonadal men and women
may be associated with an improvement in mood and depressive
symptoms.
• HPA and steroid abnormalities may contribute to
suppression of transcription of the BDNF gene
• Glucocorticoid receptors are found in high density in the
hippocampus.
• Binding of these hippocampal glucocorticoid receptors by
cortisol during chronic stress states such as major depression
may decrease BDNF synthesis and may result in volume loss
in stress-sensitive regions such as the hippocampus.
• The chronic activation of monoamine receptors by
antidepressants appears to have the opposite effect of stress
and results in an increase in BDNF transcription.
 Pharmacological effects
1. Amine uptake blockade
• NE transporter blockers acts on CNS also block
reuptake of NE at nerve endings in ANS.
• MAOI increase NE in SN terminals.
• Peripheral sympathomimetic effects
• Chronic use of MAOI can decrease BP
 2. sedation
• Common CNS effect of TCA and some heterocyclic
agents, especially mirtazapine & 5 HT antagonist
nefazodone & trazodone
• MAOI, SSRI, buprupion cause CNS stimulating effect
3. Muscarinic receptor blockade
• All TCA particularly with amitriptylin & doxepin
• Atropine ike ADRs with nefazodone, amoxapin &
maprotiline
• Atropine like effects minimal with SSRIs, bupripion &
othr heterocyclics
 4. CVS effects
• Most commonly with TCA including hypotension
from alpha adrenoceptorblockade & depression of
cardiac conduction
• May lead to arrythmias
• Cardiotoxicity with overdose of venlafaxine
5. Seizures
• TCA, MAOI lower the convulsive threshold
• Overdose may cause seizures
• Maprotiline & SSRI also cause seizure at high dose
 Clinical Indications
Depression
• both acute and long-term treatment of major
depression.
• Since antidepressants may not achieve their maximum
benefit for 1–2 months or longer, it is not unusual for a
trial of therapy to last 8–12 weeks at therapeutic doses.
• Once an adequate response is achieved, continuation
therapy is recommended for a minimum of 6–12
months to reduce the substantial risk of relapse.
 Anxiety Disorders
• PTSD, OCD, social anxiety disorder, GAD, and panic disorder
• antidepressants do not carry the risks of dependence and tolerance
that may occur with the benzodiazepines.
• Clomipramine and several of the SSRIs are approved for the treatment
of OCD, and they are moderately effective. Behavior therapy is usually
combined with the antidepressant for additional benefits.
• Several SSRIs and venlafaxine are approved for the treatment of social
anxiety. The efficacy of the SSRIs in the treatment of social anxiety is
greater in some studies than their efficacy in the treatment of MDD.
• SSRIs are considered first-line treatment for PTSD and can benefit a
number of symptoms including anxious thoughts and hypervigilance
nightmares, and avoidance of situations that remind the patient of the
trauma
 Pain Disorders
• antidepressants possess analgesic properties independent of their mood
effects
• treatment of neuropathic and other pain conditions
• Medications that possess both norepinephrine and 5-HT reuptake blocking
properties are often useful in treating pain disorders. Ascending corticospinal
monoamine pathways appear to be important in the endogenous analgesic
system. In addition, chronic pain conditions are commonly associated with
major depression. TCAs continue to be commonly used for some of these
conditions, and SNRIs are increasingly used.
• duloxetine was approved for the treatment of chronic joint and muscle pain.
• milnacipran is approved for the treatment of fibromyalgia in the USA and for
MDD in other countries.
• Other SNRIs, eg, desvenlafaxine, are being investigated for a variety of pain
conditions from postherpetic neuralgia to chronic back pain.
 Premenstrual Dysphoric Disorder
• anxiety, depressed mood, irritability, insomnia, fatigue, and a
variety of other physical symptoms.
• These symptoms are more severe than those typically seen in
premenstrual syndrome (PMS) and can be quite disruptive to
vocational and interpersonal activities.
• The SSRIs are known to be beneficial to many women with
PMDD, and fluoxetine and sertraline are approved for this
indication.
• Treating for 2 weeks out of the month in the luteal phase may
be as effective as continuous treatment.
• The rapid effects of SSRIs in PMDD may be associated with
rapid increases in pregnenolone levels.
 Smoking Cessation
• Bupropion as a treatment for smoking cessation.
• patients taking bupropion appear to experience fewer mood
symptoms and possibly less weight gain while withdrawing
from nicotine dependence. Bupropion appears to be about
as effective as nicotine patches in smoking cessation. The
mechanism by which bupropion is helpful in this application
is unknown, but the drug may mimic nicotine’s effects on
dopamine and norepinephrine and may antagonize nicotinic
receptors.
• Nicotine is also known to have antidepressant effects in some
people, and bupropion may substitute for this effect.
• Nortriptyline has been shown to be helpful in smoking
cessation, but the effects have not been as consistent as
those seen with bupropion.
 Eating Disorders
• Antidepressants appear to be helpful in the
treatment of bulimia but not anorexia. Fluoxetine
was approved for the treatment of bulimia and
other antidepressants have shown benefit in
reducing the binge-purge cycle.
• Bupropion may have some benefits in treating
obesity. Nondepressed, obese patients treated with
bupropion were able to lose somewhat more
weight and maintain the loss relative to a similar
population treated with placebo.
 Other Uses for Antidepressants

• Enuresis in children is an older labeled use for some TCAs, but

they are less commonly used now because of their side effects.
• The SNRI duloxetine for urinary stress incontinence.
• Many of the serotonergic antidepressants appear to be helpful
for treating vasomotor symptoms in perimenopause.
Desvenlafaxine for the treatment of these vasomotor symptoms
alongwith SSRIs, venlafaxine, and nefazodone
• SSRIs are known to delay orgasm in some patients. For this
reason, SSRIs are sometimes used to treat premature ejaculation.
• bupropion has been used to treat sexual adverse effects
associated with SSRI use, although its efficacy for this use has not
been consistently demonstrated in controlled trials
Selective Serotonin Reuptake Inhibitors
• inhibition of the serotonin transporter (SERT)
• Fluoxetine, sertraline, and citalopram, paroxetine, fluvoxamine
& Escitalopram
• highly lipophilic
• Fluoxetine is metabolized to an active product, norfluoxetine,
which may have plasma concentrations greater than those of
fluoxetine
• elimination half-life of norfluoxetine is about three times
longer than fluoxetine and contributes to the longest half-life
of all the SSRIs. As a result, fluoxetine has to be discontinued 4
weeks or longer before an MAOI can be administered to
mitigate the risk of serotonin syndrome.
 Pharmacodynamics
• SERT is a glycoprotein with 12 transmembrane regions
embedded in the axon terminal and cell body membranes
of serotonergic neurons
• extracellular serotonin binds to receptors on the
transporter, conformational changes occur in the
transporter and serotonin, Na+ , and Cl- are moved into the
cell.
• Binding of intracellular K+ then results in the release of
serotonin inside the cell and return of the transporter to its
original conformation
• SSRIs allosterically inhibit the transporter by binding the
SERT receptor at a site other than the serotonin binding site.
• 80% of the activity of the transporter is inhibited
• The SSRIs do not bind aggressively to histamine, muscarinic,
or other receptors.
 Adverse Effects
• SSRIs enhance serotonergic tone, not just in the brain but
throughout the body.
• Increased serotonergic activity in the gut is commonly
associated with nausea, gastrointestinal upset, diarrhea,
and other gastrointestinal symptoms
• Gastrointestinal adverse effects usually emerge early in the
course of treatment and tend to improve after the first week
• Increasing serotonergic tone at the level of the spinal cord
and above is associated with sexual dysfunction. The sexual
effects often persist as long as the patient remains on the
antidepressant but may diminish with time.
• Other adverse effects related to the serotonergic
effects of SSRIs and vortioxetine include an increase
in headaches and insomnia or hypersomnia.
• Some patients gain weight while taking SSRIs,
particularly paroxetine.
• Sudden discontinuation of short half-life SSRIs such
as paroxetine and sertraline is associated with a
discontinuation syndrome in some patients
characterized by dizziness, paresthesias, and anxiety,
tremors, beginning 1 or 2 days after stopping the
drug and persisting for 1 week or longer.
• Citalopram overdose cause QT prolongation
• Most antidepressants are category C agents
by the FDA teratogen classification system.
• There is an association of paroxetine with
cardiac septal defects in first trimester
exposures. Thus, paroxetine is a category D
agent.
Serotonin-Norepinephrine Reuptake Inhibitors

• Two classes of antidepressants act as

combined serotonin and norepinephrine
reuptake inhibitors:
1. selective serotonin-norepinephrine reuptake
inhibitors (SNRIs)
2. TCAs.
 1. Selective serotonin-norepinephrine
reuptake inhibitors
• Binds to transporter for both serotonin & NE
• Enhancing the actions of both
neurotransmitters
• Differ from TCA in lacking significant blocking
effects on peripheral receptors
• Donot block histamine, muscarinic and alpha
adrenergic receptors
Duloxetine, venlafaxine, Milnacipran
 TriCyclic Antidepressants
• Inhibit the reuptake of transporters
responsible for the termination of synaptic
action of both NE & 5HT in brain
• Potentiation of neurotransmitter action at
synaptic receptors
Amitriptyline. Clomipramine, imipramine
 ADRS & TOXICITY
• serotonergic adverse effects associated with SSRIs
• increased blood pressure and heart rate, and CNS
activation, such as insomnia, anxiety, and agitation.
• Duloxetine is rarely associated with hepatic toxicity
in patients with a history of liver damage.
• dose-related increase in blood pressure has been
seen more commonly with the immediate-release
form of venlafaxine than with other SNRIs
• discontinuation syndrome with SNRIs
• Anticholinergic effects such as dry mouth, constipation,
urinary retention, blurred vision, and confusion. (TCA)
• They are more common with tertiary amine TCAs such as
amitriptyline and imipramine than with the secondary
amine TCAs desipramine and nortriptyline.
• The potent α-blocking property of TCAs often results in
orthostatic hypotension.
• H1 antagonism by the TCAs is associated with weight gain
and sedation.
• The TCAs are class 1A antiarrhythmic agents and are
arrhythmogenic at higher doses.
• Sexual effects are common, particularly with highly
serotonergic TCAs such as clomipramine.
• The TCAs have a prominent discontinuation syndrome
characterized by cholinergic rebound and flulike symptoms.
 5HT receptor modulator
• The major ani depressant actions of nefazodone &
trazodone appear tp result from block of 5HT2A
receptor (GPCR) located in several CNS regions
including neocortex
• Antagonism is associated with both antianxiety and
antidepressant action
• also blocks SERT weakly
• Nefazodone, trazodone
• Vortioxetine Antagonist at 5-HT3, 5-HT7, 5-HT1D
receptors; partial agonist at 5-HT1B receptor,
agonist at 5HT1A receptor; inhibits SERT
 ADRS
• most common adverse effects are sedation and
gastrointestinal disturbances.
• treatment of insomnia with trazodone bcz of its sedative
effect
• gastrointestinal effects appear to be dose-related and are less
pronounced than those seen with SNRIs or SSRIs.
• Sexual effects are uncommon with nefazodone or trazodone
treatment as a result of the relatively selective serotonergic
effects of these drugs on the 5-HT2 receptor rather than on
SERT
• nefazodone and trazodone are α-blocking agents and may
result in a dose-related orthostatic hypotension in some
patients.
• Nefazodone has been associated with hepatotoxicity,
including rare fatalities and cases of fulminant hepatic failure
 Other heterocyclic AD
• A number of antidepressants do not fit neatly into
the other classes.
• Among these are bupropion, mirtazapine,
amoxapine, vilazodone, and maprotiline
• Bupropion has a unicyclic unique structure that
results in a different side-effect profile than most
antidepressants.
• Bupropion somewhat resembles amphetamine in
chemical structure and, like the stimulant, has
central nervous system (CNS) activating properties
• Mirtazapine like bupropion, is one of the few antidepressants
not commonly associated with sexual effects.
• Mirtazapine, amoxapine, and maprotiline have tetracyclic
structures.
• Amoxapine is the N-methylated metabolite of loxapine, an
older antipsychotic drug.
• Amoxapine and maprotiline share structural similarities and
side effects comparable to the TCAs.
• As a result, these tetracyclics are not commonly prescribed in
current practice.
• Their primary use is in MDD that is unresponsive to other
agents.
• Vilazodone has a multi-ring structure that allows it to bind
potently to the serotonin transporter but minimally to the
dopamine and norepinephrine transporter.
 ADRs
• Amoxapine is sometimes associated with a
parkinsonian syndrome due to its D2-blocking action.
• Mirtazapine has significant sedative effect.
• Maprotiline has a moderately high affinity for NET and
may cause TCA-like adverse effects and, rarely,
seizures.
• Bupropion is occasionally associated with agitation,
insomnia, and anorexia.
• Vilazodone may have somewhat higher rates of
gastrointestinal upset, including diarrhea and nausea,
than the SSRIs.
 Monoamine Oxidase Inhibitors
• Increase brain amine levelby interferring with their
metabolism in the nerve ending
• Results in increase in vesicular stores of NE and 5HT
• rarely used in clinical practice because of toxicity and
potentially lethal food and drug interactions
• primary use now is in the treatment of depression
unresponsive to other antidepressants.
Phenelzine, selegiline, tranylcypromine, moclobemide
 ADRs
• most common adverse effects of the MAOIs leading to discontinuation of these
drugs are orthostatic hypotension and weight gain.
• the irreversible nonselective MAOIs are associated with the highest rates of
sexual effects of all the antidepressants.
• Anorgasmia is fairly common with therapeutic doses of some MAOIs.
• The amphetamine-like properties of some MAOIs contributes to activation,
insomnia, and restlessness in some patients.
• Phenelzine tends to be more sedating than either selegiline or tranylcypromine.
• Confusion is also sometimes associated with higher doses of MAOIs.
• Because they block metabolism of tyramine and similar ingested amines, MAOIs
may cause dangerous interactions with certain foods and with serotonergic drugs
.
• sudden discontinuation syndrome manifested in a delirium-like presentation
with psychosis, excitement, and confusion.
 Interactions
• pharmacodynamic interaction of MAOIs with
serotonergic agents including SSRIs, SNRIs,
and most TCAs along with some analgesic
agents such as meperidine. These
combinations of an MAOI with a serotonergic
agent may result in a life-threatening
serotonin syndrome
 1. Serotonin Syndrome

• serotonin syndrome occurs when overdose with a single

drug, or concurrent use of several drugs, results in excess
serotonergic activity in the central nervous system.
• overstimulation of 5-HT receptors in the central gray nuclei
and the medulla.
• Symptoms range from mild to lethal and include a triad of
cognitive (delirium, coma), autonomic (hypertension,
tachycardia, diaphoreses), and somatic (myoclonus,
hyperreflexia, tremor) effects.
• Most serotonergic antidepressants should be discontinued
at least 2 weeks before starting an MAOI.
• Fluoxetine, because of its long half-life, should be
discontinued for 4–5 weeks before an MAOI is initiated.
Conversely, an MAOI must be discontinued for at least 2
weeks before starting a serotonergic agent
 diagnosis
• The diagnosis can be made in patients with a history
of exposure to a serotonergic drug plus one or more
of the following:
 spontaneous clonus
 inducible clonus with agitation and diaphoresis
 ocular clonus with agitation and diaphoresis
 tremor and hyperreflexia
 Hypertonia
 temperature over 38 C with ocular or inducible
clonus.
 Management
• Management consists of immediate discontinuation of
serotonergic agents, hydration, and supportive care to
manage blood pressure, hyperpyrexia, and respiratory
and cardiac complications.
• Sedation is best facilitated with benzodiazepines.
• Refractory cases may respond to the antidote,
cyproheptadine, which must be given orally or via
gastric tube.
• The effectiveness of cyproheptadine is unproven, but
multiple case reports support its use in patients who
do not respond to sedation and supportive care.
 2. MAOI & tyramine
• An MAOI prevents the breakdown of tyramine in the gut, and
this results in high serum levels that enhance peripheral
noradrenergic effects, including raising blood pressure
dramatically.
• Patients on an MAOI who ingest large amounts of dietary
tyramine may experience malignant hypertension and
subsequently a stroke or myocardial infarction.
• Thus, patients taking MAOIs require a low-tyramine diet and
should avoid foods such as aged cheeses, tap beer, soy products,
and dried sausages, which contain high amounts of tyramine
• Similar sympathomimetics also may cause significant
hypertension when combined with MAOIs.
• over-the-counter cold preparations that contain
pseudoephedrine and phenylpropanolamine are contraindicated
in patients taking MAOIs.