Antidepressants work primarily by increasing levels of serotonin, norepinephrine, and dopamine in the brain. The most common classes are SSRIs, SNRIs, TCAs, and MAOIs. SSRIs are usually the first line treatment due to their efficacy and safety. They work by selectively inhibiting the reuptake of serotonin. SNRIs also inhibit norepinephrine reuptake. TCAs and MAOIs are less commonly used now due to their side effect profiles. Common side effects across classes include nausea, sleep disturbances, and sexual dysfunction.

1. Antidepressant and
Antipsychotics
GK

2. Antidepressants are used primarily to treat major depressive disorder (MDD), although they
are also indicated for the treatment of many other neuropsychiatric conditions.
The most widely used classes of antidepressants are
selective serotonin reuptake inhibitors (SSRIs),
serotonin-norepinephrine reuptake inhibitors (SNRIs),
monoamine oxidase inhibitors (MAOIs),
tricyclic antidepressants (TCAs).
Most of these drugs work by increasing levels of
serotonin,
norepinephrine,
dopamine within the synaptic cleft.
SSRIs are the first-line treatment for the vast majority of patients with
depression because of their efficacy and favorable side-effect profile.
While MAOIs and TCAs also have a high degree of efficacy, they are no longer
widely used because of their undesirable side-effect profiles.

8. -(TCAs) and selective (SSNRIs)
block SERTs and
norepinephrine transporters
(NETs), inhibiting the reuptake
of 5-HT and NE respectively.
– Bupropion inhibits the
reuptake of NE by blocking
NETs.
– Serotonin antagonist and
reuptake inhibitors (SARIs)
block postsynaptic 5-HT2
receptors and weakly inhibit
the reuptake of 5-HT (by
blocking SERTs at higher
doses).
1. Increasing neurotransmitter release -Mirtazapine increases the release of NE and 5-HT into the synaptic cleft by blocking the
presynaptic alpha-2 adrenergic receptors. It also inhibits postsynaptic 5-HT2 and 5-HT3 receptors, reducing some of the side
effects of increased serotonergic activity (e.g., nausea, sleep disturbances).
2. Decreasing neurotransmitter breakdown - Monoamine oxidase (MAO) inhibitors decrease the breakdown
3. Inhibiting the reuptake of neurotransmitters and thereby increasing their concentration within the synaptic cleft
– (SSRIs) block serotonin transporters (SERTs), inhibiting the reuptake of 5-HT.

9. SELECTIVE SEROTONIN REUPTAKE INHIBITORS
The selective serotonin reuptake inhibitors (SSRIs) are a group of anti-
depressant drugs that specifically inhibit serotonin reuptake, having 300- to
3000-fold greater selectivity for the serotonin transporter, as compared to the
norepinephrine transporter. This contrasts with the tricyclic anti- depressants
(TCAs) and serotonin/norepinephrine reuptake inhibitors (SNRIs) that
nonselectively inhibit the reuptake of norepinephrine and serotonin.
Moreover, the SSRIs have little blocking activity at muscarinic,  -adrenergic,
and histaminic H1 receptors.
Because they have different adverse effects and are relatively safe in
overdose, the SSRIs have largely replaced TCAs and monoamine oxidase
inhibitors (MAOIs) as the drugs of choice in treating depression.

10. •Mechanism of action: inhibition of serotonin reuptake in synaptic cleft →
• Fluoxetine
• Paroxetine
• Sertraline
• Citalopram
• Escitalopram
• Fluvoxamine
•Indications
• Major depressive disorder (first-line therapy)
• Generalized anxiety disorder (GAD)
• Obsessive-compulsive disorder (OCD)
• Post-traumatic stress disorder (PTSD)
• Panic disorder
• Premature ejaculation
• Premenstrual dysphoric disorder
• Binge-eating disorder
• Bulimia nervosa - (only fluoxetine is approved for bulimia).
• Social Anxiety disorder

12. • Antidepressants, including SSRIs, typically take at
least 2 weeks to produce significant improvement in
mood, and maximum benefit may require up to 12
weeks or more.
• A patient must be treated with an adequate dosage
for at least 6 weeks before considering changing the
treatment, although adverse effects due to their
synaptic effects occur soon after taking the drug.
• Marked interindividual variations in the blood levels
of an antidepressant with a given dose may be
observed due to individual differences in the activity
of drug-metabolizing enzymes. Clinically, these
differences likely underlie the observed differences
in the rates of response and of adverse effects..

13. Pharmacokinetics
• All of the SSRIs are well absorbed after oral administration. 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 occurs extensively.
• Fluoxetine has the longest half-life (50 hours), and the half-life of its active metabolite S-
norfluoxetine is quite long, averaging 10 days. Fluoxetine and paroxetine are potent inhibitors of a
CYP450 isoenzyme (CYP2D6). Other CYP450 isoenzymes (CYP2C9/19, CYP3A4, CYP1A2) are
involved with SSRI metabolism and may also be inhibited to various degrees by the SSRIs.

14. 1. Sleep disturbances: Paroxetine and fluvoxamine are generally more sedating
than activating, and they may be useful in patients who have difficulty in sleeping.
Conversely, patients who are fatigued or complaining of excessive somnolence
may benefit from one of the more activating SSRIs, such as fluoxetine or
sertraline.
2.Sexual dysfunction: Sexual dysfunction, which may include loss of libido,
delayed ejaculation, and anorgasmia, is common with the SSRIs.
3.Use in children and teenagers: Antidepressants should be used cautiously in
children and teenagers, because of reports of suicidal ideation as a result of
SSRI treatment. Fluoxetine, sertraline, and fluvoxamine are approved for use in
children to treat obsessive–compulsive disorder, and fluoxetine and
escitalopram are approved to treat childhood depression.
4. Overdose and toxicity: Overdose with SSRIs does not usually cause cardiac
arrhythmias, with the exception of citalopram, which may cause QT prolongation.
Seizures are a possibility because all antidepressants may lower the seizure
threshold.

15. • Early side effects (onset and resolution typically within 1 week of therapy start)
• Headache
• Diarrhea, nausea, vomiting
• Activating effects (e.g., agitation, anxiety, insomnia)
• Late side effects
• Sexual dysfunction (e.g., anorgasmia, ↓ libido, erectile or ejaculatory dysfunction)
• SIADH
• Serotonin syndrome
• Can be caused by any drug that increases serotonin levels (
• Serotonin syndrome caused by SSRIs alone typically manifests with mild symptoms
(e.g., nausea, mild tremor).
• Increased risk of occurrence and greater severity of symptoms when
coadministered with another serotonergic agent(e.g., MAOIs)
• Differential diagnosis: poisoning or overdose from concomitant use of substances
(e.g., ethanol, salicylates) that may cause similar symptoms to serotonin
syndrome (e.g., altered mental status)
• Motor disorders (e.g., tremors, bruxism)

17. SEROTONIN/NOREPINEPHRINE
REUPTAKE INHIBITORS
•Mechanism of action: inhibition of serotonin and norepinephrine reuptake
in synaptic cleft → ↑ serotonin and norepinephrinelevels
•Drugs
• Venlafaxine
• Duloxetine
• Desvenlafaxine
• Levomilnacipran
• Milnacipran
•Indications
• Major depressive disorder (second-line therapy)
• Generalized anxiety disorder
• Neuropathic pain (e.g. diabetic neuropathy)
• Duloxetine and milnacipran specifically: fibromyalgia
• Stress incontinence in women: duloxetine
• Venlafaxine specifically: social anxiety disorder, OCD, panic disorder,
and PTSD

18. Depression is often accompanied by
chronic painful symptoms, such as
backache and muscle aches, against
which SSRIs are also relatively ineffective.
This pain is, in part, modulated by serotonin and
norepinephrine pathways in the central nervous system.
Both SNRIs and the TCAs, with their dual inhibition of
both serotonin and norepinephrine reuptake, are
sometimes effective in relieving pain associated with
diabetic peripheral neuropathy, postherpetic neuralgia,
fibromyalgia, and low back pain.
The SNRIs, unlike the TCAs, have little activity at  -
adrenergic, muscarinic, or histamine receptors and,
thus, have fewer of these receptor-mediated adverse
effects than the TCAs. The SNRIs may precipitate a
discontinuation syndrome if treatment is abruptly
stopped.

19. A. Venlafaxine and desvenlafaxine
Venlafaxine is an inhibitor of serotonin reuptake and, at medium to higher doses, is an
inhibitor of norepinephrine reuptake. Venlafaxine has minimal inhibition of the CYP450
isoenzymes and is a substrate of the CYP2D6 isoenzyme. Desvenlafaxine is the active,
demethylated metabolite of venlafaxine. The most common side effects of venlafaxine
are nausea, headache, sexual dysfunction, dizziness, insomnia, sedation, and
constipation. At high doses, there may be an increase in blood pressure and heart rate.
The clinical activity and adverse effect profile of desvenlafaxine are similar to those of
venlafaxine.
B. Duloxetine
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 with duloxetine, including nausea, dry mouth, and constipation. Insomnia,
dizziness, somnolence, sweating, and sexual dysfunction are also seen. Duloxetine may increase blood
pressure or heart rate. Duloxetine is a moderate inhibitor of CYP2D6 isoenzymes and may increase
concentrations of drugs metabolized by this pathway, such as antipsychotics. Duloxetine may rarely
cause hepatotoxicity.

20. Levomilnacipran
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 of levomilnacipran 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.

21. •TRICYCLIC ANTIDEPRESSANTS Mechanism of action
1. Inhibition of neurotransmitter
reuptake: TCAs and amoxapine are
potent inhibitors of the neuronal reuptake
of norepinephrine and serotonin into
presynaptic nerve terminals. Maprotiline
and desipramine are relatively selective
inhibitors of norepinephrine reuptake.
2. Blocking of receptors: TCAs also block
serotonergic,  -adrenergic, histaminic,
and muscarinic receptors. It is not known
if any of these actions produce the
therapeutic benefit of the TCAs.
However, actions at these receptors are
likely responsible for many of their
adverse effects. Amoxapine also blocks
5-HT2 and dopamine D2 receptors.
•Mechanism of action: inhibition
of serotonin and norepinephrine reuptake in synaptic

22. •Indications
• Major depressive disorder (third-
or fourth-line therapy)
• Neuropathic pain (e.g., peripheral
neuropathy, diabetic
neuropathy, postherpetic neuralgia)
• Chronic pain (including fibromyalgia)
• Migraine prophylaxis
• Clomipramine specifically: OCD
• Imipramine specifically: nocturnal
enuresis (limited use due to side effects)
•Side effects
•Orthostatic hypotension
•Cardiotoxicity due to Na+ channel inhibition in
the myocardium: changes in cardiac conductivity
velocity, arrhythmias, prolonged QT interval (predisposes
to torsades de pointes), wide QRS complex
•Tremor
•Respiratory depression
•Hyperpyrexia
•Anticholinergic symptoms due to blockage of
muscarinic cholinergic receptors (more common with tertiary
amines)
• Cardiovascular: tachycardia, arrhythmia (including ventri
cular fibrillation), hypotension
• CNS: confusion, hallucinations,
sedation, coma, seizures (confusion and hallucinations a
re most commonly seen in older patients)
• Gastrointestinal: intestinal ileus, constipation
• Genitourinary: urinary retention
• General: xerostomia, mydriasis, hyperthermia, dry skin
•Certain TCAs (e.g., clomipramine) are associated
with hyperprolactinemia

24. B. Actions
The TCAs improve mood, in 50% to 70% of individuals with major depression. The onset of the mood
elevation is slow, requiring 2 weeks or longer. Patient response can be used to adjust dosage. Tapering of
these agents is recommended to minimize discontinuation syndromes and cholinergic rebound effects.
C. Therapeutic uses
The TCAs are effective in treating moderate to severe depression. Some patients with panic disorder also
respond to TCAs. Imipramine is used as an alternative to desmopressin or nonpharmacologic
therapies (enuresis alarms) in the treatment of bedwetting in children.
The TCAs, particularly 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. Low doses of TCAs, especially doxepin, can be used to treat insomnia.
D. Pharmacokinetics
TCAs are well absorbed upon oral administration. As a result of their variable first-pass metabolism in the
liver, TCAs have low and inconsistent bioavailability.
These drugs are metabolized by the hepatic microsomal system (and, thus, may be sensitive to agents
that induce or inhibit the CYP450 isoenzymes) and conjugated with glucuronic acid. Ultimately, the TCAs
are excreted as inactive metabolites via the kidney. These drugs are highly lipid soluble and have a
relatively long half-life.

25. Adverse effects
Blockade of muscarinic receptors leads to blurred vision, xerostomia, urinary retention,
sinus tachycardia, constipation, and aggravation of angle-closure glaucoma.
These agents affect cardiac conduction similar to typical of class IA antiarrhythmics
(quinidine) and may precipitate life-threatening arrhythmias in an overdose situation. They
thus contribute toward the narrow therapeutic index of tricyclic antidepressants. This
property is a major pharmacological distinction between the older tricyclic compounds and
the newer generation compounds.
The TCAs also block  -adrenergic receptors, causing orthostatic hypotension, dizziness,
and reflex tachycardia.
Sedation is related to the ability of these drugs to block histamine H1 receptors.
Weight gain is a common adverse effect of the TCAs.
Sexual dysfunction occurs in a minority of patients, and the incidence is lower than that
associated with the SSRIs.
All antidepressants, including TCAs, should be used with caution in patients with bipolar
disorder, even during their depressed state, because antidepressants may cause a switch to
manic behavior.

26. •Mechanism of action: inhibition
of serotonin and norepinephrine reuptake in synaptic
cleft → ↑ serotonin and norepinephrine levels
•Drugs
• Secondary amines
• Nortriptyline
• Desipramine
• Protriptyline
• Amoxapine
• Tertiary amines
• Amitriptyline
• Clomipramine
• Doxepin
• Imipramine
• Trimipramine
•Indications
• Major depressive disorder (third- or fourth-line therapy)
• Neuropathic pain (e.g., peripheral neuropathy, diabetic
neuropathy, postherpetic neuralgia)
• Chronic pain (including fibromyalgia)
• Migraine prophylaxis
• Clomipramine specifically: OCD
• Imipramine specifically: nocturnal enuresis (limited use due to
side effects)
•Side effects
• Orthostatic hypotension
• Cardiotoxicity due to Na+ channel inhibition in
the myocardium: changes in cardiac conductivity
velocity, arrhythmias, prolonged QT
interval (predisposes to torsades de pointes), wide QRS
complex
• Tremor
• Respiratory depression
• Hyperpyrexia
• Anticholinergic symptoms due to blockage of
muscarinic cholinergic receptors (more common with
tertiary amines)
• Cardiovascular: tachycardia, arrhythmia (including v
entricular fibrillation), hypotension
• CNS: confusion, hallucinations,
sedation, coma, seizures (confusion and hallucinati
ons are most commonly seen in older patients)
• Gastrointestinal: intestinal ileus, constipation
• Genitourinary: urinary retention
• General: xerostomia, mydriasis, hyperthermia,
dry skin

27. Tricyclic antidepressant toxicity
•Mechanism
• Cardiac fast sodium channel inhibition
• Muscarinic ACh receptor inhibition
• A1-adrenergic receptor inhibition
• H1 receptor inhibition
• GABAA inhibition
•Clinical features: Most signs and symptoms are related to anticholinergic effects.
• Prolonged QTc, arrhythmias
• Seizures
• Coma
• Respiratory depression
• Hyperpyrexia
•Diagnosis: clinical diagnosis
• ECG
• Prolonged QRS
• Prolonged QTc
• Urine immunoassay: detection of TCA
•Management
• Supportive treatment (secure airways, oxygenation, monitoring, fluid resuscitation)
• Activated charcoal within 2 hours of ingestion (only if airway has been secured)
• Sodium bicarbonate for treatment and prevention of cardiac arrhythmia: monitor with ECG (QRS ≥ 100 ms or ventricular
arrhythmias)
• Benzodiazepines for seizures

29. VII. MONOAMINE OXIDASE INHIBITORS
Monoamine oxidase (MAO) is a mitochondrial enzyme found in nerve and other tissues, such as the gut and liver. In
the neuron, MAO 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.
The MAOIs may irreversibly or reversibly inactivate the enzyme, permitting neurotransmitters to escape degradation
and, therefore, to accumulate within the pre- synaptic neuron and leak into the synaptic space.
•Mechanism of action
• Nonselective inhibition of monoamine oxidase → ↓ breakdown of epinephrine, norepinephrine, serotonin,
and dopamine →↑ levels of epinephrine, norepinephrine, serotonin, and dopamine
• Selegiline: selective MAO-B inhibitor → mainly ↓ breakdown of dopamine → ↑ levels of dopamine
•Drugs
• Tranylcypromine
• Phenelzine
• Selegiline
• Isocarboxazid
•Indications
• Major depressive disorder (third- or fourth-line therapy): particularly effective treatment for atypical
depression
• Parkinson disease: selegiline (as an adjunct to carbidopa-levodopa)
• Anxiety

30. •Side effects
• CNS stimulation
• Sexual dysfunction
• Orthostatic hypotension
• Weight gain
• Hypertensive crisis with ingestion of foods
containing tyramine
• Examples: aged cheeses, smoked/cured meats, alcoholic
beverages (especially beer and red wine), dried fruits, fava beans, chocolate
beans, chocolate
• Tyramine stimulates the sympathetic nervous system by releasing
other neurotransmitters, such as noradrenaline, from vesicles into
the synaptic cleft.
•Drug interactions: risk of serotonin syndrome if used concomitantly with
other serotonergic drugs, linezolid, SSRIs, TCAs, meperidine, dextromethorphan, and St.

31. A. Mechanism of action
Most MAOIs, such as 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.
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.
The MAOIs, therefore, show a high incidence of
drug–drug and drug–food interactions. Selegiline
administered as the transdermal patch may produce
less inhibition of gut and hepatic MAO at low doses
because it avoids first-pass metabolism.

32. Actions
Although MAO is fully inhibited after several days of treatment, the
antidepressant action of the MAOIs, like that of the SSRIs, SNRIs, and TCAs,
is delayed several weeks. Selegiline and tranylcypromine have an
amphetamine-like stimulant effect that may produce agitation or insomnia.
Therapeutic uses
The MAOIs are indicated for depressed patients who are unresponsive or
intolerant of other antidepressants. Because of their risk for drug–drug and
drug–food interactions, the MAOIs are considered last-line agents in many
treatment settings.
Pharmacokinetics
These drugs are well absorbed after oral administration. Enzyme regen-
eration, when irreversibly inactivated, varies, but it usually occurs several
weeks after termination of the drug. Thus, when switching anti- depressant
agents, a minimum of 2 weeks of delay must be allowed after termination of
MAOI therapy and the initiation of another antide- pressant from any other
class. MAOIs are hepatically metabolized and excreted rapidly in urine.

33. Adverse effects
Severe and often unpredictable side effects, due to drug–food and drug–drug interactions, limit
the widespread use of MAOIs. For example, tyramine, which is contained in foods, such as aged
cheeses and meats, liver, pickled or smoked fish, and red wines, is normally inactivated by MAO
in the gut. Individuals receiving an MAOI are unable to degrade tyramine obtained from the diet.
Tyramine 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.
Patients must, therefore, be educated to avoid tyramine-containing foods. Other possible adverse
effects of treatment with MAOIs include drowsiness, orthostatic hypotension, blurred vision, dry
mouth, and constipation.
SSRIs should not be coadministered with MAOIs due to the risk of serotonin syndrome. 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 an MAOI is initiated. In addition, the MAOIs have many other critical drug interactions, and
caution is required when administering these agents concurrently with other drugs. summarizes
the side effects of the antidepressant drugs..

36. V. ATYPICAL ANTIDEPRESSANTS
The atypical antidepressants are a mixed group of agents that have actions at several different sites. This
group includes bupropion [byoo-PROE- pee-on], mirtazapine [mir-TAZ-a-peen], nefazodone [ne-FAZ-oh-done],
trazodone [TRAZ-oh-done], vilazodone [vil-AZ-oh-done], and vortioxetine [vor-TEE-ox-e-teen].
A. Bupropion
Bupropion is a weak dopamine and norepinephrine reuptake inhibitor that is used to alleviate the symptoms of
depression. Bupropion is also useful for decreasing cravings and attenuating withdrawal symptoms of nicotine
in patients trying to quit smoking. Side effects may include dry mouth, sweating, nervousness, tremor, and a
dose- dependent increased risk for seizures. It has a very low incidence of sexual dysfunction. Bupropion is
metabolized by the CYP2B6 path- way and has a relatively low risk for drug–drug interactions, given the few
agents that inhibit/induce this enzyme. Use of bupropion should be avoided in patients at risk for seizures or
those who have eating disorders such as bulimia.
B. Mirtazapine
Mirtazapine enhances serotonin and norepinephrine neurotransmission by serving as an antagonist at central
presynaptic  2 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.
Sedation, increased appetite, and weight gain frequently occur.

37. Bupropion
•Mechanism of action: not fully understood, but thought
to increase dopamine and norepinephrine levels via reuptake inhibition
•Indications
• Smoking cessation: used in conjunction with counseling and nicotine replacement
• Major depressive disorder
•Side effects
• Stimulant effect
• Tachycardia, palpitations
• Weight loss
• Neuropsychiatric symptoms: insomnia, agitation, headache
• Reduction of seizure threshold: Bupropion should be avoided in patients at increased risk
for seizure (e.g., history
of epilepsy, anorexia/bulimia, alcohol or benzodiazepine withdrawal).
• Does not cause sexual side effects
• Dry mouth
•Drug interactions: risk of serotonin syndrome if used concomitantly with other serotonergic
drugs

38. Mirtazapine
•Mechanism of action
• Selective α2-adrenergic
antagonist → ↑ serotonin and norepinephrine release
• 5-HT2 and 5-HT3 receptor antagonists → ↑ effect of serotonin on free 5-
HT1 receptor is the likely cause of antidepressant action
• H1 antagonist
•Indications: major depressive disorder, especially in patients who are
underweight and/or who have insomnia
•Side effects
• ↑ Appetite and weight gain: can also be a desired effect
• Sedation (due to H1 antagonism): can also be a desired effect
• ↑ Serum cholesterol and triglyceride levels
• Minimal sexual side effects
• Dry mouth
•Drug interactions: risk of serotonin syndrome if used concomitantly with
other serotonergic drugs

39. Nefazodone and trazodone
These drugs are weak inhibitors of serotonin reuptake and are also
antagonists at the postsynaptic 5-HT2a receptor. Both agents are highly
sedating, probably because of their potent histamine H1-blocking activity.
Trazodone is commonly used off-label for the management of insomnia.
These drugs cause gastrointestinal dis- turbances. Sexual effects are limited
except that trazodone has been associated with priapism in men.
Nefazodone has been asso- ciated with a rare risk for hepatotoxicity. Both
agents also have mild-to-moderate  1 receptor antagonism, contributing to
orthosta- sis and dizziness.

40. Vilazodone
Vilazodone is a serotonin reuptake inhibitor and a 5-HT1a receptor 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 of vilazodone is similar to the SSRIs, including a risk for
discontinuation syndrome if abruptly stopped.
Vortioxetine
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
vortioxetine. The common adverse effects include nausea, constipation,
and sexual dysfunction, which may be expected due to its serotonergic
mechanisms.

42. St. John's wort
•Description
• A flowering plant (Hypericum perforatum)
used as a medicinal herb for depression
• Because of its over-the-counter availability
and significant drug interactions, it is
important to be familiar with this dietary
supplement.
•Indication: Although not approved by the FDA,
which considers it a dietary supplement, there are
some studies that support St. John's wort is superior
superior to placebo in treating mild depression.
•Drug interactions
• Inducer of cytochrome P450
• Serotonin syndrome if taken with drugs that
increase serotonin levels

43. Antidepressant discontinuation syndrome
•Description: symptoms caused by abrupt withdrawal or dose reduction of
antidepressants taken for ≥ 4 weeks
•Clinical features
• Flu-like symptoms (fatigue, lethargy, malaise, muscle aches, headaches, diarrhea,
sweating)
• Insomnia (vivid dreams, nightmares)
• Nausea
• Imbalance (gait instability, dizziness, lightheadedness, vertigo)
• Sensory disturbances (paresthesias, electric shock sensations)
• Hyperarousal (anxiety, agitation)
• Dysphoria, irritability
• Psychosis (especially with MAOI discontinuation)
•Timing
• Typically occurs within 3 days after drug cessation
• Symptoms usually subside within 1–2 weeks
•Diagnosis: is primarily based on history and clinical features.
•Treatment: Restart antidepressant therapy at the original dose and begin tapering slowly.

44. Serotonin syndrome - a life-threatening condition caused by serotonergic overactivity,
Cause: drugs that increase serotonin levels
• Antidepressants (e.g., MAOIs, SSRIs, SNRIs, TCAs,vortioxetine, vilazodone, trazodone)
• Anxiolytics (e.g., buspirone)
• Opioids (e.g., tramadol, meperidine)
• NMDA receptor antagonists (e.g., dextrometorphan)
• Recreational stimulants (e.g., MDMA, cocaine)
• Serotonin receptor antagonists (e.g., ondansetron)
• Serotonin receptor agonists (e.g., triptane)
• Antibiotics (e.g., linezolid)
• Herbals (e.g., St. John's wort)
• Risk-increasing factors
• Concurrent use of two or more serotonergic drugs

45. •acute symptom onset (< 24 hours after intake of a
drug that increases serotonin levels)
• Classic triad
• Neuromuscular excitability
• Autonomic dysfunction
• Altered mental status
• General: diaphoresis, hyperthermia
• Cardiovascular: hypertension, tachycardia
• Gastrointestinal: nausea, vomiting, diarrhea
• Psychiatric: delirium, psychomotor
agitation, anxiety
• Neurological: hypertonia (especially in the
lower
extremities), hyperreflexia, myoclonus, tremo
r, clonus, horizontal ocular
clonus, mydriasis, seizure, coma

46. •Treatment
• Immediate discontinuation of serotonergic drugs
• Supportive care
• Antihypertensives, fluid replacement
• Benzodiazepines for sedation
• Cyproheptadine
• H1, 5-HT1A, and 5-HT2A receptor antagonists
• Used for cases of serotonin syndrome that do
not respond to supportive care
• Cooling measures: ice packs and cold compresses
•Prognosis: resolves within 24 hours with treatment [19]

49. Lithium
Lithium is a psychiatric medication used primarily as a first-line therapy for bipolar disorder. It is also used
in treatment-resistant depression to augment antidepressants. The specific mechanism by which lithium acts to
stabilize mood is not definitively known, but it is thought to be due to inhibition of the phosphoinositol cascade.
Common side effects include gastrointestinal distress (nausea, diarrhea), polyuria, polydipsia, and tremor. Lithium
therapy has a very narrow therapeutic index; frequent monitoring is therefore required to prevent toxicity.
The onset of therapeutic effect takes 2 to 3 weeks.
Antipsychotic drugs and benzodiazepines can be used in the initial stages of the disease to control acute
agitation.
Anticonvulsants such as valproic acid, carbamazepine, and lamotrigitne have been used extensively
either alone or as adjunct to lithium therapy.
Although many cellular processes are altered by treat- ment with lithium, the mode of action is unknown.
The therapeutic index of lithium is extremely low (0.5 to 1.4 mmol/L), and levels above 2 mmol/L can be
toxic. The levels of lithium should be monitored regularly. Common adverse effects at therapeutic levels
may include headache, dry mouth, polydipsia, polyuria, polyphagia, edema, weight gain, GI distress fine
hand tremor, dizziness, fatigue, dermatologic reactions, and sedation.

50. Pharmacodynamics
•Mechanism of action: While the mechanism of action has not been definitively
established, inhibition of the phosphoinositol cascade is thought to result in mood
stabilization.
•Steady state: usually reached 4–5 days after initiation or a change in dosage
Pharmacokinetics
•95% of lithium is excreted by the kidneys.
•It is freely filtered at the glomerulus and mostly reabsorbed in the proximal convoluted
tubule via sodium channels. [
Indications
•First-line therapy for bipolar disorder
• Mood stabilization in patients with acute mania
• Maintenance therapy
•Augmentation in treatment-resistant depression

51. General adverse effects
Adverse effects occur at therapeutic levels (0.4–1.0 mEq/L) but tend to be more severe at peak serum
concentration of the drug.
Nonspecific
•Nausea, diarrhea
•Weight gain
•Dry oral mucosa
•Leukocytosis
Motor
•Fine tremor
• Nonprogessive, symmetric, fine postural tremor in the distal ends of upper extremities
• Typically occurs when lithium therapy is started or the dose is increased but can occur at any time
during the course of treatment
• Often decreases spontaneously over time
•Muscle weakness
Dermal
•Acne
•Worsening psoriasis
•Hair thinning

52. Cardiac
•ECG changes: T-wave depressions (most common), U waves, repolarization abnormalities
•Sinus node dysfunction (most commonly sinus bradycardia)
Thyroid
•Hypothyroidism (often subclinical)
• Thyroid function tests should be performed every 6–12 months during ongoing treatment
treatment
• Lithium-induced hypothyroidism, should be treated with replacement therapy
(levothyroxine).
• There is usually no need to discontinue lithium therapy.
•Lithium-induced hyperparathyroidism
• Caused by the elevation of the calcium-sensing setpoint of the parathyroid glands and
induction of parathyroid hormone production
• Leads to hypercalcemia
•Goiter (particularly in second and third trimester of pregnancy)

53. Renal
•Nephrogenic diabetes insipidus
• Pathophysiology: lithium interferes with ADH signaling
→ ↓ aquaporins (water channels) on the collecting duct cell's surface
→ ↓ water molecules are reabsorbed and kidneys are unable to
concentrate urine → ↑ free water excretion
• Clinical features: polyuria, nocturia, and polydipsia → ↑ risk
of dehydration and subsequent lithium toxicity
•Chronic interstitial nephritis (lithium-associated nephropathy)
• Interstitial fibrosis, focal nephron atrophy, tubular cysts with chronic use
• Risk correlates with the cumulative dose and duration of lithium use.
• Often occurs in the setting of nephrogenic DI
• Can progress to chronic kidney disease

54. Lithium toxicity
Toxicity occurs at serum levels > 1.5 mEq/L.
Causes
•Increase in dosage (lithium has a narrow therapeutic window)
•Renal impairment from any cause
•Low effective circulating volume (e.g., due to dehydration, loop diuretic use, cirrhosis, congestive heart failure)
•Medications that can precipitate lithium toxicity by increasing renal absorption of lithium:
• Thiazide diuretics
• NSAIDs (except aspirin)
• ACE inhibitors
•Other medications: tetracyclines, cyclosporines, metronidazole
Clinical features
•Gastrointestinal
• Nausea, vomiting, and diarrhea
• Further fluid loss may exacerbate lithium toxicity.
•Neuromuscular
• Altered mental status, confusion
• Somnolence, coma
• Delirium, encephalopathy, psychomotor impairment
• Coarse tremors, seizures, fasciculations, myoclonic jerks,
• Ataxia, slurred speech, nystagmus
• Hyperreflexia
•Acute renal failure
Sodium depletion results in
increased renal reabsorption of
lithium and increased chance for
toxicity. Sodium depletion is
increased by low-salt diets,
thiazide diuretics, furosemide,
ethacrynic acid, or severe
diarrhea or vomiting.

55. •Lithium toxicity
• Discontinuation of lithium
• Hydration with isotonic fluid (0.9% NaCl solution) and electrolyte correction to promote
promote lithium clearance
• Hemodialysis: first-line treatment for severe lithium toxicity
• Indications
• Serum lithium concentration > 5.0 mEq/L
• Serum lithium concentration > 4.0 mEq/L with kidney dysfunction
• Altered mental status, seizures, and/or life-threatening arrhythmias
• Hemodialysis should be continued until serum lithium concentration is < 1.0
mEq/L or for a minimum of 6 hours (if the serum lithium concentration cannot be
measured).
• Ventilatory support if required
• Whole bowel irrigation with polyethylene glycol can also be considered.
• Activated charcoal does not prevent the absorption of lithium.

56. Contraindications
•Absolute contraindications
• Advanced renal failure (creatinine clearance < 30 mL/min)
• Severe cardiovascular disease
•Relative contraindications
• Concurrent diuretic use
• Dehydration, sodium depletion
• Desired pregnancy/pregnancy: lithium can freely cross the placental barrier, inevitably
resulting in fetal lithium exposure
• ↑ Risk of miscarriage and neonatal complications (e.g., longer duration of hospital
stays, higher rate of CNS and neuromuscular complications) [10][11]
• Teratogenicity (especially in the first trimester): ↑ risk of
cardiovascular malformations (in particular Ebstein anomaly)
• If lithium is needed during pregnancy, aim for the minimum effective dose and
monitor serum levels regularly.
• LARCs are generally the preferred method of contraception because they are easy to
use and have low failure rates. [12]

58. 1.A 25-year-old woman has a
long history of depres- sive
symptoms accompanied by body
aches and pain secondary to a
car accident. Which of the fol-
lowing drugs might be useful in
this patient?
A. Fluoxetine
B. Sertraline
C. Phenelzine
D. Duloxetine

59. D. Duloxetine is an SNRI that
can be used for depression
accompanied by symptoms of
pain. SSRIs (fluoxetine and
sertraline) and MAOIs
(phenelzine) have little activity
against pain syndromes

60. A 51-year-old woman with symptoms
of major depression also has angle-
closure glaucoma. Which
antidepressant should be avoided in
this patient?
A. Amitriptyline
B. Bupropion
C. Mirtazapine
D. Fluvoxamine

61. A. Because of its potent
antimuscarinic activity, amitriptyline
should not be given to patients with
glaucoma because of the risk of
acute increases in intraocular
pressure. The other antidepressants
all lack antagonist activity at the
muscarinic receptor.

62. Antipsychotics are a heterogeneous group of substances used primarily to
treat schizophrenia, psychosis, mania, delusions, and states of agitation.
The term neuroleptics was formerly used interchangeably with antipsychotics because early
antipsychotic drugs induced apathy, quiescence, and reduced psychomotor activity, but newer
antipsychotic drugs have a decreased risk of these effects.
The antipsychotic effect of first-generation antipsychotics (also called typical antipsychotics,
e.g., haloperidol) is based on D2 antagonism,
Second-generation antipsychotics (also called atypical antipsychotics) interact with several receptors (e.g.,
D2, D3, D4, 5-HT).
Extrapyramidal symptoms, which include acute dystonia, akathisia, and tardive
are the most common side effects of first-generation antipsychotics.
Metabolic side effects (e.g., weight gain, insulin resistance), on the other hand, are more typical of second-
generation antipsychotics. A potentially life-threatening side effect of both first-generation and second-
generation antipsychotics is neuroleptic malignant syndrome, which manifests with fever, muscle rigidity,
autonomic instability, and mental status changes.

63. Description
•First-generation antipsychotics (also called typical antipsychotics): block D2 receptor → ↑ cAMP
• High-potency antipsychotics have a strong antipsychotic effect even at relatively low doses, but they also
also more commonly cause neurologic side effects (e.g., extrapyramidal symptoms) than low-potency
antipsychotics.
• Low-potency antipsychotics more commonly cause anticholinergic, antihistamine, and sympathetic α1-
blockade effects.
• Stored in fat tissue (lipid soluble) and, therefore, only slowly eliminated from the body.
•Second-generation antipsychotics (also called atypical antipsychotics): most are 5-HT2 and D2 antagonists with
varying α and H1 receptoreffects
•All antipsychotics, except for clozapine (used for treatment-resistant schizophrenia), have similar
clinical effectiveness.
•The choice of drug depends on the side effect profile of the antipsychotic drugs and the patient's clinical status.
status.
•SGAs are preferred in many cases because they carry a lower risk of EPS; however, in some patients (e.g., those
those with significant metabolic risk factors), FGAs may be more suitable.

72. Extrapyramidal symptoms (EPS)
•Definition: a collection of movement disorders that are typically due to disruption
of dopaminergic pathways in the basal ganglia, resulting
in bradykinesia, rigidity, dystonia, athetosis, chorea, ballismus, akathisia, tics,
and tremors
•Etiology
• All antipsychotics that interact with the D2 receptor may cause EPS, but
the probability of this side effect is significantly higher with high-potency
FGAs than with SGAs or low-potency FGAs.
• Metoclopramide, although not an antipsychotic, may also cause EPS.
• Anticonvulsants (e.g., carbamazepine) may also cause movement disorders.
• Antidepressants
•Pathophysiology: Inhibition of the nigrostriatal dopaminergic pathways results in EPS.
• First-generation high-potency antipsychotics: D2antagonism → EPS
• Second-generation antipsychotics: weaker D2antagonism → fewer EPS