Drugs for Depressive Disorders
Kaukab Azim, MBBS, PhD
Drug List
Antidepressants
MAO inhibitors
Tricyclics
Atypicals
SSRIs
SNRIs
Fluoxetine
Paroxetine
Sertraline
Citalopram
Venlafaxine
Non Selective Selective
Imipramine
Amitriptamine
Clomipramine
Trazodone
Bupropion
Phenelzine
Mirtazapine
* This drug will be covered in another lecture
Selegiline*
Classification of Depressive Disorders
(from DSM IV text revision)
Type
Features
Major depressive disorder
(endogenous depression – about 20% of all
depressions)
Depression is autonomous and is unresponsive to
changes in life. Biological factors seem important
(family history).
It can occur as a single episode or may be
recurrent.
Dysthymic disorder
A mood disorder with chronic (long-term) depressive
symptoms that are present most of the day, more days
than not, for a period of at least two years
Any depressive disorder that does not meet the
criteria of a specific disorder. Examples are
Depressive disorder not otherwise specified  Minor depressive disorder
 Recurrent brief depressive disorder
Pharmacology of Antidepressants
Mechanism of action
Short-term mechanisms
The molecular action of most antidepressants is an increase
availability of NE and/or 5-HT in the synaptic cleft of brain
neurons, or an altered response of these monoamine
receptors. This is most likely due to the following
mechanisms:
1. Tricyclic antidepressants (TCADs)
Blockade of reuptake of 5-HT and NE.
2. Monoamine oxidase inhibitors
Non selective inhibition of both MAO A and MAO B (Phenelzine).
Selective inhibition of MAO B. (Selegiline).
3.Atypical
(
also
called
antidepressants (HEADS)
heterocyclic)
Mechanisms are often unclear but in most cases the final
result is an effect on monoamines or monoamine receptors.
4.Selective serotonin reuptake inhibitors (SSRIs)
Selective blockade of the reuptake of 5-HT (at therapeutic
doses about 80% of the activity of the transporter is inhibited)
5.Selective serotonin & norepinephrine reuptake
inhibitors (SNRIs)
Blockade of the reuptake of 5-HT and NE.
Pharmacology of Antidepressants
Mechanism of action
Long-term mechanisms
☞ Over time the increase availability of monoamines in
the synaptic cleft likely causes a down-regulation of
postsynaptic CNS receptors (mainly adrenergic and
serotonergic). This occurs after 1-4 weeks of
treatment when the therapeutic effect becomes
evident.
☞ Long term changes ultimately increase BDNF(Brain
derived neurotrophic factor) which increases
neurogenesis, mainly in the hippocampus.
Pharmacology of Antidepressants
Pharmacological effects
➼ All available antidepressants are equally effective in the general depressed patient
population.
➼ All antidepressants have the same delayed onset (1-4 weeks) of therapeutic effects.
➼ Some central and many peripheral effects of antidepressants result from blockade
of serotonergic, adrenergic, cholinergic and histaminergic receptors.
Pharmacokinetics and administration
➼ Variable oral bioavailability (0.25-0.70)
➼ High or very high Vd.
➼ Extensive metabolism by the liver (some metabolites are active).
➼ Half-lives are long (8-36 hours). Fluoxetine has a half life of about 50 hours and an
active metabolite with a half life of about 10 days.
Administration: PO, IM , IV, transdermal patch (selegiline).
Reuptake and Blocking Activity and Receptor Blocking Activity of Antidepressants
Drug
Amine pump block
Receptor Block
5-HT
NE
DA
5-HT2
Alpha-1
M
H1
Imipramine
++
+
0
0/+
+
++
+
Amitriptyline
++
++
0
0/+
+++
+++
++
Clomipramine
+++
++
0
+
++
+
+
Trazodone
+
0
0
++
++
0
0/+
Bupropion
0
0/+
+
0
0
0
0
Mirtazapine
0
+
0
+
Alpha2
0
++
Fluoxetine
+++
0
0
0/+
0
0
0
Paroxetine
+++
0
0
0
0
+
0
Citalopram
+++
0
0
0
0
0
0
++
++
0/+
0
0
0
0
Tricyclics
Heterocyclics
SSRIs
SNRIs
Venlafaxine
Heterocyclic (atypical) Antidepressant
TRAZODONE
Mechanism of action
➼ The drug is thought to act primarily as an antagonist at 5-HT2-A and 5-HT2-C
presynaptic receptors, so increasing serotonin release.
Adverse effects
➼ Drowsiness (up to 40%, likely related to blockade of 5-HT2 A, alpha-1 and H1
receptors).
➼ Postural hypotension
➼ Xerostomia (up to 30%)
➼ Priapism(A persistent painful erection), sexual dysfunctions.
Therapeutic uses
➼ Depression (as a second choice drug, mainly in patients with agitation and
insomnia).
➼ As an unlabeled hypnotic, since it is not associated with tolerance or dependence.
Heterocyclic (atypical) Antidepressant
BUPROPION
Mechanism of action
➼ It is still poorly understood. It stimulates the release and blocks the reuptake of NE and DE. The drug is
closely related to diethylpropion (an amphetamine-like drug).
➼ The drug has virtually no direct effects on the serotonin system.
Adverse effects
➼
➼
➼
➼
Insomnia (up to 30%), tremor (up to 20%),
Seizures (dose-dependent effect).
Appetite reduction, weight loss (up to 28 %)
Xerostomia, constipation (.10%)
Contraindications
➼ Current or past epilepsy
➼ Conditions predisposing to a low threshold for seizures (head trauma, alcohol misuse, diabetes, etc)
➼ Use of certain drugs (theophylline, neuroleptics, glucocorticoids)
Therapeutic uses
➼ Depression (second choice drug, or as an adjunct with other therapies)
➼ Attention deficit hyperactivity disorder (second choice drug).
➼ Smoking cessation (20-25% of success)
Heterocyclic (atypical) Antidepressant
MIRTAZAPINE
Mechanism of action
➼ Blockade of presynaptic alpha-2 receptors, which results in increased release of
norepinephrine from noradrenergic nerve endings, and of serotonin from serotonergic nerve
endings.
➼ Blockade of 5-HT2A/C presynaptic receptors.
☛ (It is not known which one of those two actions is more important for the antidepressant
effect)
➼ Blockade of H1 receptors (which likely mediates the sedative effects)
Adverse effects
➼ Sedation and drowsiness (up to 40%), dizziness.
➼ Constipation (10%), appetite stimulation, weight gain (up to 15%)
Therapeutic uses
➼ Depression (second choice drug, but sometimes highly effective)
Adverse Effects of Antidepressants
All antidepressants increase the risk for
suicide in patients 25 and under. Since
failure to start treatment is also a risk
for
suicide,
cognitive
pharmacological
behavioral
therapy
and
are
recommended with close supervision.
Adverse effects of
tricyclic antidepressants
CNS effects
➼ Drowsiness (the most common CNS effect), sedation, lassitude(Heaviness), fatigue,
dysphoria, dizziness
➼ Tremor, paresthesias, seizures (tricyclics lower the seizure threshold)
➼ Pseudoparkinsonism (rare)
Autonomic effects
➼ Anticholinergic effects (memory
constipation, urinary retention)
impairment,
xerostomia,
blurred
vision,
Cardiovascular effects
➼ Postural hypotension
➼ Cardiac arrhythmias, due to antimuscarinic and quinidine-like actions [patients with
long Q-T intervals are at greater risk]
➼ Cardiomyopathy (after long-term use).
Adverse effects of
tricyclic antidepressants
Other adverse effects
➼Weight gain (mainly with paroxetine). The mechanism
is unknown
➼Sexual dysfunction
➼SIADH(Syndrome
of
inapropriate
anti-diuretic
hormone) secretion (rare)
Over dosage
➼Tricyclics have a narrow therapeutic index.
Manifestations
include
agitation,
delirium,
hyperpyrexia, convulsions, coma, cardiac arrhythmias,
circulatory collapse
Adverse effects of
MAO inhibitors
➼Postural hypotension (common), edema.
➼Headache, insomnia, nightmares, nervousness.
➼Switch into mania ( about 10% of patients with bipolar
disorders)
➼Weight gain
➼Sexual dysfunction
antidepressants).
(the
highest
rates
of
all
the
➼Dangerous interactions with certain foods and with
serotonergic drugs.
➼Hypertensive crisis is rare but can be lethal.
GI effects
Adverse effects of
SSRIs and SNRIs
➼ Anorexia, nausea and vomiting (these are the most common reason
for discontinuation, but usually dissipated in a week),
➼ Diarrhea (up to 20%) (due to increased serotonergic activity in the
gut)
CNS effects
➼ Sexual dysfunction (up to 50%)
➼ Sleep disturbances (up to 30%) (insomnia, more vivid and memorable
dreams, morning sleepiness).
➼ Seizures (in patients at risk)
➼ Extrapyramidal
symptoms
movements), dystonias) (rare).
(tremor,
akathisia(Involuntary
Adverse effects of
SSRIs and SNRIs
Other adverse effects
➼ Weight gain (mechanism unknown)
➼ SIADH (rare)
➼ Serotonin syndrome
➼ SSRI (mainly fluoxetine and paroxetine) are inhibitors of the
cytochrome P450 system and therefore can increase the effects of
several drugs given concomitantly.
➼ Discontinuation syndrome (abrupt discontinuation of an SSRI or SNRI
can cause a variety of symptoms that can be quite distressing. These
include dizziness, nausea and vomiting, flulike symptoms, irritability
and anxiety.)
Antidepressant induced Sexual
Dysfunction
Incidence
➼ Overall frequency 30-50%.
➼ Incidence seems the highest with SSRIs/SNRIs (mainly paroxetine and
fluoxetine) and the lowest with bupropion and mirtazapine.
Pathophysiology
➼ Serotonin is mainly an inhibitory neurotransmitter in the CNS
Symptoms and signs
➼ In males: erectile dysfunction, priapism, delayed ejaculation
➼ In females: decreased vaginal lubrication and clitoral congestion.
➼ In both sexes: decreased libido, partial or complete anorgasmia(Excitement)
Therapy
➼ Reduction to minimal effective dose (often difficult to find)
➼ Changing antidepressant
➼ Adding drugs which improve sexual function (sildenafil, dextroamphetamine,
methylphenidate, amantadine, etc)
The Serotonin Syndrome
Clinical course and prognosis
➼Upon discontinuation of the offending drug most cases resolve
within 24 hours, but the syndrome can be fatal (likely because
of malignant hyperthermia).
Therapy
➼For mild cases: discontinuation of the offending drug.
➼For more serious cases:
a.
b.
c.
d.
Benzodiazepines for agitation and somatic effects.
Serotonin antagonists (cyproheptadine) or atypical neuroleptics
with serotonin blocking activity (like olanzapine).
Beta-blockers for tachycardia and autonomic instability.
Dantrolene for hyperthermia.
Contraindications and Precautions of
Antidepressants
Tricyclics and heterocyclics
➼ Seizure disorders, Parkinson’s disease
➼ Suicidal ideation
➼ Cardiac disease ( Long Q-T intervals, arrhythmias, myocardial
infarction, etc.)
➼ Glaucoma
➼ Gastroesophageal reflux disease, hiatal(opening OR aperture)
hernia
➼ Prostatic hypertrophy
➼ Pregnancy (tricyclics are included in FDA pregnancy risk category D)
➼ Children
➼ Elderly (antimuscarinic effects may be greatly enhanced)
Contraindications and Precautions of
Antidepressants
SSRIs, SNRIs
➼ Seizure disorders
➼ Suicidal ideation
➼ Hepatic disease (liver clearance can be decreased)
➼ Anorexia (SSRIs can decrease hunger)
➼ Sleep disturbances
➼ Concurrent therapy with other antidepressants, benzodiazepines,
betablockers, methadone, etc.
➼ Children (about 1 out of 50 children become more suicidal)
➼ Pregnancy (only paroxetine is classified in FDA pregnancy risk
category D)
Therapeutic Uses of Antidepressants
➼Most antidepressants are of equivalent efficacy in patients with
major depressive disorder, when administered in comparable
dose.
➼When one antidepressant is ineffective the addition of another
antidepressant can be useful (so called augmentation therapy)
➼Drugs used effectively in augmentation therapy include lithium,
bupropion, buspirone, lamotigrine and triiodothyronine.
➼A maintenance therapy with an antidepressant should be
maintained for least 9-12 months.
➼Approximately 65-70% of patients with varying types of depression
improve with drug therapy compared with 30-40% who improve
with placebo.