Antidepressants

Antidepressants
Dr. S. Parasuraman M.Pharm., Ph.D.,
Senior Lecturer, Faculty of Pharmacy,
AIMST University,
Bedong 08100, Malaysia.

Depression
• Major depression and mania are two extremes of
affective disorders which refer to a pathological change
in mood state.
• The symptoms of depression are intense feelings of
sadness, hopelessness, and despair 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, rapid thought and
speech patterns, extreme self-confidence, and impaired
judgment.

Classification of anti-depresent
• Reversible inhibitors of MAO-A (RIMAs): Moclobemide,
Clorgyline
• Tricyclic antidepressants (TCAs):
– NA + 5-HT reuptake inhibitors: Imipramine, Amitriptyline,
Trimipramine, Doxepin, Dothiepin, Clomipramine
– Predominantly NA reuptake inhibitors: Desipramine,
Nortriptyline, Amoxapine, Reboxetine
• Selective serotonin reuptake inhibitors (SSRis): Fluoxetine,
Fluvoxamine, Paroxetine, Sertraline, Citalopram, Escitalopram
• Atypical antidepressants: Trazodone, Mianserin, Mirtazapine,
Venlafaxine, Duloxetine, Tianeptine, Amineptine, Bupropion
• 5-HT2Antagonists: trazodone and nefazodone

• AC, adenylyl cyclase;
• 5-HT, serotonin;
• CREB, cAMP response element-
binding (protein);
• DAG, diacyl glycerol;
• IP3, inositol trisphosphate;
• MAO, monoamine oxidase;
• NET, norepinephrine
transporter;
• PKC, protein kinase C;
• PLC, phospholipase
Depression

Hypothesis of major depression
• Depression appears to be associated with changes in
serotonin or norepinephrine signaling in the brain (or
both) with significant downstream effects.
• Most antidepressants cause changes in amine signaling.

MAO inhibitors
• MAO is a mitochondrial enzyme involved in the oxidative
deamination of biogenic amines (Adr, NA, DA, 5-HT). Two
isoenzyme forms of MAO have been identified.
• Dopamine is degraded equally by both isoenzymes.
• MOA inhibitors inhibits the metabolism of biological amines
to cause disproportionate elevation of mood.
MOA isoenzymes Active against Inhibited by
MAO-A 5-HT and NA Clorgyline,
Moclobemide
MAO-B Phenylethylamine Selegiline

MAO inhibitors
• The nonselective MAO inhibitors causes
– elevate the mood in depressed patients
– progress to hypomania and mania
– excitement and hypomania may be produced in nondepressed
individuals
• The drugs themselves stay in the body for relatively short
periods, but their effects last for 2-3 weeks after
discontinuation.
• MOA inhibitors are 'hit and run' drugs-return of MAO
activity depends on synthesis of fresh enzyme; tissue
monoamine levels remain elevated long after the drug has
been largely eliminated.

MAO inhibitors
• Interactions: MAO inhibitors inhibits a number of other
enzymes as well, and interact with many food constituents
and drugs.
– Cheese reaction: MAO inhibiters indirectly acting sympathomimetic
amines escape degradation in intestinal wall and liver  reaching
into systemic circulation they displace large amounts of NA from
transmitter loaded adrenergic nerve endings  hypertensive crisis,
cerebrovascular accidents. Alpha blockers (e.g.: phentolamine,
prazosin) or chlorpromazine can be used for treatment of chees
reaction.
– Cold and cough remedies: Cough syrup contains ephedrine or
other sympathomimetics  cause hypertensive reaction.
– Reserpine, guanethidine, tricyclic antidepressants: Excitement,
rice in BP and body temperature can occur when given these drugs
to patient on MOA inhibitor (due to NA release or uptake blocking
action).

MAO inhibitors
– Levodopa: Excitement and hypertension, due to increase in
biological half life of DA and NA.
– Antiparkinsonian anticholinergics: Hallucinations and symptoms
similar to those of atropine poisoning occur.
– Barbiturates, alcohol, opioids, antihistamines: respiration may fail.
– Pethidine: High fever, sweating, excitation, delirium, convulsions,
and severe respiratory depression may occur.

Reversible inhibitors of MAO-A
Moclobemide
• It is reversible and selective MAO-A inhibitor with short duration of
action and full MAO activity is restored within 1-2 days of stopping the
drug.
• Its effective antidepressant, comparable to TCAs.
• It lacks the anticholinergic, sedative, cognitive, psychomotor and
cardiovascular adverse effects of typical TCAs and is safer in overdose.
• ADR: nausea, dizziness, headache, insomnia, rarely excitement and
liver damage.
• Use: Alternative for TCAs for mild to moderate depression and social
phobia.
• Dose: 150 mg; BD or TID (Max 600 mg/ kg/ day)

TRICYCLIC ANTIDEPRESSANTS (TCAs)
Imipramine
• It is an analogue of CPZ and found during clinical trails to selectively
benefit depressed but not agitated psychotics.
• MOA:
– TCAs block norepinephrine and serotonin reuptake into the neuron.
– Inhibition of neurotransmitter reuptake: TCAs is potent inhibitors of the
neuronal reuptake of norepinephrine and serotonin into presynaptic
nerve terminals. At therapeutic concentrations, they do not block
dopamine transporters. TCAs cause increased concentrations of
monoamines in the synaptic cleft, ultimately resulting in antidepressant
effects. Maprotiline and desipramine are relatively selective inhibitors of
norepinephrine reuptake.
– Blocking of receptors: TCAs also block serotonergic, α-adrenergic,
histaminic, and muscarinic receptors. It is not known if any of these
actions produce TCAs’ therapeutic benefit.

Pharmacological action:
• Central nervous system:
• ANS: Most TCAs are potent anticholinergics-cause dry mouth, blurring
of vision, constipation and urinary hesitancy as side effect.
Normal individual Depressed patient
It induces a peculiar clumsy
feeling, tiredness, light-
headedness, sleepiness, difficulty
in concentrating and thinking,
unsteady gait, anxiety.
no mood elevation or euphoria
Little acute effects are produced,
except sedation.
After 2-3 weeks of continuous
treatment, the mood is gradually
elevated, patients become more
communicative and start taking
interest in self and surroundings.

• CVS: Effects on cardiovascular function are prominent, occur at
therapeutic concentrations and may be dangerous in overdose.
– Tachycardia: due to anticholinergic and NA potentiating actions.
– Postural hypotension: due to inhibition of cardiovascular reflexes
and α1 blockade.
– ECG changes and cardiac arrhythmias: T wave suppression or
inversion is the most consistent change.
– Arrhythmias occur in overdose due to interference with
intraventricular conduction, combination of NA potentiating + ACh
blocking actions and direct myocardial depression.

Tolerance and dependence:
• Tolerance to the anticholinergic and hypotensive effects of
imipramine-like drugs develops gradually, though antidepressant
action is sustained.
• Psychological dependence on these drugs is rare, because their
acute effects are not pleasant.
• Acute poisoning:
• Poisoning with TCA is frequent and cause excitement, delirium,
and other anticholinergic symptoms as seen in atropine
poisoning.
• Treatment for acute TCA poisoning: Gastric lavage, respiratory
assistance, fluid infusion, maintenance of BP and body
temperature. Diazepam may be given i.c. to control convulsion
and delirium and to prevent cardiac arrhythmias, propranolol/
lidocaine may be used.

Pharmacokinetics:
• TCAs are well absorbed upon oral administration. Because of
their lipophilic nature, they are widely distributed and readily
penetrate into the CNS (t1/2 is 4 to 17 hours for imipramine).
• As a result of their variable first-pass metabolism in the liver,
dosage adjustment may require at the initial treatment period is
typically 4 to 8 weeks. The dosage can be gradually reduced to
improve tolerability, unless relapse occurs.
• These drugs are metabolized by the hepatic microsomal system
and conjugated with glucuronic acid. TCAs are excreted as
inactive metabolites via the kidney.

Adverse effects:
• Blockade of muscarinic receptors leads to blurred vision,
xerostomia (dry mouth), urinary retention, sinus tachycardia,
constipation, and aggravation of narrow-angle glaucoma.
• The TCAs also block α-adrenergic receptors, causing orthostatic
hypotension, dizziness, and reflex tachycardia.
• Weight gain is a common adverse effect of the TCAs. Sexual
dysfunction, as evidenced by erectile dysfunction in men and
anorgasmia in women, occurs in a significant minority of
patients, but the incidence is still considered to be lower than
the incidence of sexual dysfunction associated with the SSRIs.

Selective Serotonin Reuptake Inhibitors (SSRis)
The major limitations of conventional TCAs are:
• Frequent anticholinergic, cardiovascular and neurological side
effects.
• Relatively low safety margin, hazardous in overdose; fatalities
common.
• Lag time of 2-4 weeks before antidepressant action manifests.
• Significant number of patients respond incompletely and some
do not respond.

• The selective serotonin reuptake inhibitors (SSRIs) are inhibit
serotonin reuptake, having 300- to 3000-fold greater selectivity for
the serotonin transporter, as compared to the norepinephrine
transporter.
• SSRIs also have little blocking activity at muscarinic, α-adrenergic,
and histaminic H1 receptors.
• 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.
• SSRIs, typically take at least 2 weeks to produce
significant improvement in mood, and maximum
benefit may require up to 12 weeks or more.

Pharmacokinetics
• All SSRI are well absorbed after oral administration.
• Food has little effect on absorption (except sertraline, for which
food will increase its absorption).
• Majority of SSRIs have plasma half –lives that range of 16-36 h.
• Metabolism by cytochrome P450 (CYP450)-dependent enzymes
and glucuronide or sulfate conjugation occur extensively.
• SSRIs may affect the metabolism of multiple medications and its
excretion of the SSRIs is primarily through the kidneys, except for
paroxetine and sertraline, which also undergo fecal excretion (35
and 50 percent, respectively).
• Dosages of all of these drugs should be adjusted downward in
patients with hepatic impairment.

Pharmacokinetics
• Fluoxetine differs from the other members of the class in two
respects. First, it has a longer half-life (50 hours) and is available
as a sustained-release preparation allowing once-weekly dosing.
• 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.
• Fluoxetine and paroxetine are potent inhibitors of a hepatic
CYP450 isoenzyme (CYP2D6) responsible for the limination of
TCAs, neuroleptic drugs, and some antiarrhythmic and β-
adrenergic antagonist drugs. Other cytochrome enzymes
(CYP2C9/19, CYP3A4, CYP1A2) are involved with SSRI metabolism
and may also be inhibited to various degrees by the SSRIs.

Therapeutic uses
• The primary indication for SSRIs is depression, for which they are
as effective as the TCAs. A number of other psychiatric disorders
also respond favorably to SSRIs, including obsessive-compulsive
disorder, panic disorder, generalized anxiety disorder,
posttraumatic stress disorder, social anxiety disorder and
premenstrual dysphoric disorder.
• Fluoxetine is approved for Bulimia nervosa.
• Fluoxetine, sertraline, and fluvoxamine are approved for use in
children to treat obsessive-compulsive disorder, and fluoxetine is
approved to treat childhood depression by US-FDA.

Adverse effects
• SSRIs are considered to have fewer and less severe adverse
effects than the TCAs and MAOIs.
• SSRIs are commonly cause headache, sweating, anxiety and
agitation, gastrointestinal effects (nausea, vomiting, diarrhea),
weakness and fatigue, sexual dysfunction, changes in weight and
sleep disturbances (insomnia and somnolence).
• Sleep disturbances: Paroxetine and fluvoxamine are generally
more sedative than other SSRI. Can be used as antidepressant.
• Sexual dysfunction: Loss of libido, delayed ejaculation, and
anorgasmia are underreported side effects. In men with erectile
dysfunction and depression, treatment with sildenafil, vardenafil,
or tadalafil may improve sexual function.

Adverse effects
• Use in children and teenagers:
– Antidepressants should be used cautiously in children and
teenagers, because about 1 out of 50 children report suicidal
ideation as a result of SSRI treatment.
– Pediatric patients should be observed for worsening
depression and suicidal thinking whenever any antidepressant
is started or its dose is increased or decreased.

Overdoses:
• Large intakes of SSRIs do not cause cardiac arrhythmias
(compared to the arrhythmia risk for the TCAs), but seizures are a
possibility because all antidepressants may lower the seizure
threshold.
• All SSRIs have the potential to cause a serotonin syndrome that
may include the symptoms of hyperthermia, muscle rigidity,
sweating, myoclonus (clonic muscle twitching), and changes in
mental status and vital signs when used in the presence of a
MAOI or other highly serotonergic drug.
• Therefore, extended periods of washout for each drug class
should occur prior to the administration of the other class of
drugs.

Discontinuation syndrome:
• All SSRIs have the potential for causing a discontinuation
syndrome after their abrupt withdrawal, the agents with the
shorter half-lives and having inactive metabolites have a higher
risk for such an adverse reaction.
• Fluoxetine has the lowest risk of causing an SSRI
discontinuation syndrome.
• Possible signs and symptoms of such a serotonin-related
discontinuation syndrome include headache, malaise and flu-like
symptoms, agitation and irritability, nervousness, and changes in
sleep pattern.

Atypical antidepressants
Trazodone:
• It is the first atypical antidepressant; selectively but less
efficiently blocks 5-HT uptake and has prominent a blocking as
well as weak 5-HT2 antagonistic action.
• It is not anticholinergic, but causes bradycardia, and doesn't
interfere with intracardiac conduction, hence it is less prone to
cause arrhythmia.
• trazodone is well tolerated and relatively safe in overdose:
seizures do not occur. Its t1/z is short (approx. 6 hr).
• ADR: Inappropriate, prolonged and painful penile erection
(priapism) occurs in few recipients resulting in impotence.

Mianserin • not inhibiting either NA or 5-HT uptake;
but blocks presynaptic alpha 2 receptors
Tianeptine • This antidepressant is reported to
increase rather than inhibit 5-HT uptake,
and is neither sedative nor stimulant.
Amineptine • Enhances 5-HT uptake
• It produces anticholinergic side effects
including tachycardia, confusion and
delirium.
• Postural hypotension, conduction
disturbances and arrhythmias can occur,
especially in patients with heart disease.
Venlafaxine • A novel antidepressant referred to as
'serotonin and noradrenaline reuptake
inhibitor' (SNRI)

USES
• Endogenous (major) depression
• Obsessive-compulsive and phobic status
• Anxiety disorders
• Neuropathic pain
• Attention deficit-hyperactivity disorder in children
• Enuresis
• Migraine
• Pruritus

Antidepressants

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Antidepressants