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IN THE NAME OF GOD
Seyed Alireza Haji seyed javadi
MD Psychiatrist
Assistant Professor and Head
Department of Psychiatry
school of Medicine
Qazvin University of Medical Science
Qazvin,Iran
Email: [email protected]
Telfax: + 98 28 33555054
‫تازه های دارویی در روانپزشکی‬
‫داروهای ضد افسردگی‬
Available Types of Pharmacotherapy
Tricyclic antidepressants (TCA) 
MAOI’s 
SSRI’s 
SNRI’s 
Atypical antidepressants 
Antidepressants
Mechanisem
• Most antidepressants block the reuptake of a neurotransmitter of one
or more of the bioamines:
serotonin, norepinephrine,
dopamine.
Tricyclic Antidepressants
• Available for more than 30 years
• Act by NE and/or 5 HT presynaptic reuptake
inhibition
• Side effects include anticholinergic effects,
orthostasis, slowing of cardiac conduction
• Secondary better than tertiary compounds
Chemistry
• Tricyclic and tetracyclic compounds are categorized primarily on the
basis of their chemical structure .The tricyclics have a three-ring
structure, hence, their name.
• The tertiary amine tricyclics, such as amitriptyline (Elavil) and
imipramine, have two methyl groups at the end of the side chain.
• These compounds can be demethylated to secondary amines, such
as desipramine (Norpramin, Pertofrane) and nortriptyline
(Aventyl, Pamelor).
• The tetracyclic compounds, maprotiline (Ludiomil) and amoxapine
(Asendin), have a four-ring central structure.
• Five tertiary amines have been marketed in the United States—
amitriptyline, clomipramine (Anafranil), doxepin (Sinequan),
imipramine, and trimipramine (Surmontil).
• The three secondary amine compounds are desipramine,
nortriptyline, and protriptyline (Vivactil).
Antidepressants
Tricyclic: Tertiary Amines
Amitriptyline (Elavil)
Clomipramine (Anafranil)
Doxepine (Sinequan)
Imipramine (Tofranil)
Trimipramine (Surmontil)
Antidepressants
Tricyclic: Secondary Amines
Desipramine (Norpramin) 
Nortriptyline (Aventyl, Pamelor) 
Protryptyline (Vivactil) 
Antidepressants
Tetracyclic
Maprotiline (Ludiomil) 
Amoxapine (Asendin) 
Side Effects – TCAs
• Most common uncomfortable side effects:
– Sedation
– Orthostatic hypotension
– Anticholinergic
• Others
–
–
–
–
–
Tremors
Restlessness, insomnia, confusion
Pedal edema, headache, and seizures
Blood dyscrasias
Sexual dysfunction
• Adverse
– Cardiotoxicity
Effects of tricyclic antidepressants on Reuptake
and 5-HT2
Tricyclic antidepressants
5-HT reuptake
Noradrenaline
reuptake
5-HT2 antagonism
Tricyclic antidepressants
Amitriptyline
Clomipramine
Desipramine
Dothiepin
Doxepin
Imiprmine
Lofipramine
Nortriptyline
+ +
++
?
+
+
-
+
++
+
+
+
+
+
+
?
+
+
Which one of the tricyclics is more selective on inhibiting reuptake of NE?
Which one of the tricyclics is more selective on inhibiting reuptake of 5-HT?
Side Effects of Tricyclic antidepressants
Relative Side effects
Amitriptyline
Amoxapine
Clomipramine
Desipramine
Dothiepin
Doxepin
Imipramine
Lofepramine
Nortriptyline
Protriptyline
Trimipramine
Sedation
Cardiotoxicity
+++
++
++
+
+++
+++
++
+
+++
+
+++
++
+
+++
+++
++
+++
+
++
+++
+++
Reuptake inhibition
Hypotension
+++
+
++
+
++
++
+++
+
0/+
+
++
AntiCholinnergic
+++
++
++
++
++
++
+++
+
++
++
++
NE
++
+++
+/++++
+
+
+
++++
+++
++++
+
5-HT
+++
+
+++
+/+
+
+++
+
+
+
+
Monoamine Oxidase Inhibitors:
History: The anti TB Iproniazide
exhibited
mood elevating properties and
latter found to inhibit MOA.
Antidepressants
Monoamine Oxidase Inhibitors (MAOIs)
• Action: Inhibits enzyme responsible for the
metabolism of serotonin, dopamine,
norepinephrine and tyramine
• Increases levels of norepinephrine and
serontonin in the CNS
• Interacts with food – low tyramine diet
Classifications of MAOIs
Either:
Hydralazine Derivatives (Phenelzine (Nardil®)
Non –hydralazine DER.(Tranylcypramine (Parnate®)
Or as irreversible non –selective (Phelzine and
Tranylcypramine) vs reversible selective ( Mclobemide)
Side Effects:↑ appetite (Phenelzine like)
↓ appetite
(Tranylcypramine; hepatotoxicity; SLE like;
Drug and Food interactions
(very important).
Drug
Non-selective
irreversible
Selective
reversible
Sedation
Anticholinergic Hypotensin
effects
Isocarboxazid
+
++
+
Phenelzine
+
++
+
Tranylcypromine
-
+
+
-
-
-
Moclobemide
Selective Serotonin Reuptake
Inhibitors
)SSRIs)
Selective Serotonin
Reuptake Inhibitors
SSRIs
– Fluoxetine (Prozac)
– Sertraline (Zoloft)
– Paroxetine (Paxil)
– Fluvoxamine (Luvox)
– Citalopram (Celexa)
– Escitalopram (Lexapro)
Side Effects – SSRIs
•
•
•
•
•
•
•
Headache
Anxiety
Transient nausea
Vomiting
Diarrhea
Weight gain
Sexual dysfunction
SSRIs
• Usually given in morning, unless sedation
occurs
• Higher doses, except fluoxetine, can produce
sedation.
• Paroxetine associated with weight gain
Selective Serotonin
Reuptake Inhibitors
•
•
•
•
•
Produce response rates close to 70%
Safer and better tolerated than TCA’s
Given once daily
Starting and therapeutic doses often similar
Most common side effects include GI symptoms,
HA, insomnia, anxiety, and sexual dysfunction
• Five available in the U.S.
Effect of SSRIs on Reuptake and 5-HT2
5-HT reuptake
Selective serotonin reuptake
inhibitors
Citalopram
Fluoxetine
Fluvxamine
Paroxetine
Sertraline
+
+
+
+
+
Noradrenaline
reuptake
-
5-HT2
antagonists
-
What is the clinical significant of the antagonistic effect on 5-HT2 receptors?
Side Effects of SSRI
• Almost have no cardiovascular manifestations as
compared to TCA.
• Nausea and vomiting and decrease appetite How?
•
Insomnia and anxiety (with Fluoxetine ; Citalopram; but
not with Paroxetine. So What?
•
Impotence and sexual dysfunction (in male and female)
• Decrease weight.
Dosing and Administration
• In general, therapeutic effects are not dose
related.
• There are no data that suggest that the presence
of therapeutic levels of any SSRI correlates with
plasma levels and subsequent clinical response.
• Nevertheless, patients may vary considerably in
the amount of medication they need to derive
clinical benefit.
Fluoxetine
• Fluoxetine is available in 10- or 20-mg pulvules, as 10-mg
tablets, as 90-mg enteric-coated capsules for onceweekly administration, and as an oral concentrate of 20
mg/5 mL.
• The suggested starting dose of fluoxetine in patients with
major depression is 20 mg per day. Effective doses for the
treatment of major depression have been reported, ranging
from 5 to 80 mg per day in dose-finding trials.
• Preclinical trials of fluoxetine in bulimia nervosa showed efficacy greater
than placebo at 60 mg per day.
• Treatment of OCD is also usually at higher doses than those used in
major depression, with doses of 20 to 80 mg per day most commonly
used.
• Treatment of panic disorder is often initiated at less than 5 to 10 mg per
day with a gradual upward dose titration.
• Treatment of social anxiety disorder or premenstrual dysphoric disorder
is often started at 10 to 20 mg per day. Dose is adjusted upward as
needed.
• Starting doses of 10 mg per day are often used in treating children,
adolescents, or elderly patients. Adjustment upward is based on clinical
response and tolerance of side effects.
Citalopram and Escitalopram
• Citalopram is available in 10-, 20-, and 40-mg-size tablets. The 20- and
40-mg-size tablets are scored. Citalopram is also available in an oral
solution at a concentration of 10 mg/5 mL. Escitalopram is available in
10- and 20-mg-size tablets, both of which are scored. An oral solution of
5 mg/5 mL is available as well.
•
•
The manufacturer recommends a starting dose for citalopram of 20 mg per day,
with the expectation of generally increasing the dose to 40 mg per day, which, in
clinical practice, is typically done after at least 1 week on the initial dosing. Highly
anxious patients or those with increased sensitivities to side effects of
medications may benefit from starting with the 10-mg tablet.
The recommended starting dose of escitalopram is 10 mg per day. In clinical
trials, the 20–mg-per-day dose did not offer any added benefit, but individual
patients are often observed to benefit from the higher dose. If the dose is to be
increased to 20 mg, this should generally occur no sooner than after 1 week on
the initial dose. Because the 10-mg tablet is scored, 5 mg as a starting dose, if
required, is available.
• Many patients are observed to do well if citalopram or escitalopram is
taken after meals for the first few days. After that period, they can take
the medication with or without food.
Sertraline
• Sertraline is available in scored tablets of 25-, 50-, and 100-mg strengths.
The oral concentrate is formulated at a concentration of 20 mg/mL with
a12 percent alcohol content and must be diluted before use
• Initial dosing for major depressive disorder and OCD is typically at 50 mg
per day, with escalation to 100 mg per day after 4 to 7 days of treatment.
• Initial treatment of panic disorder, social anxiety disorder, and PTSD is
more typically 25 mg per day.
• Children in OCD studies were started at 25 mg per day, whereas
adolescents in OCD studies were started at 50 mg per day.
• Treatment of premenstrual dysphoric disorder is usually started at 50 mg
per day given daily or during the 2 weeks of the luteal phase.
• Individual patients may demonstrate improved tolerability starting at
lower doses. Not uncommonly, patients require an upward titration of
the dose.
• The dose range in most patients with anxiety or affective
disorders is typically 100 to 200 mg a day, although some
patients respond to 50 mg per day. Patients with OCD often
require higher doses for full therapeutic effect.
Fluvoxamine
•
•
•
•
•
Fluvoxamine is available in 25-, 50-, and 100-mg scored tablets and 100- and 150-mg
controlled release capsules. Adults with OCD are often started at a dose of 50 mg
administered at bedtime. The dose may be increased by 50 mg every 4 to 7 days.
The effective dosing range in premarketing trials with OCD was 100 to 300 mg per day,
although, clearly, some patients do respond to higher doses.
The manufacturer suggests dividing the daily dose if it exceeds 100 mg per day, although
many patients tolerate doses larger than 100 mg as a single dose. Initial upward titration is
often easier with a split-dose regimen.
Treatment of OCD in adolescents and children should start at 25 mg per day with 25–mgper-day increases every 4 to 7 days. The effective dosing range in premarketing studies was
50 to 200 mg per day. Adolescents often require a dose close to that used in adults,
whereas children, perhaps owing to higher plasma fluvoxamine levels, may respond to the
lower portion of the dosing range. Due its short half-life, total daily doses of fluvoxamine
greater than 50 mg should be administered as a split dose. Using the controlled release
formulation obviates this need for divided doses.
Dosing for disorders other than those for which fluvoxamine is approved in the United
States is usually initiated at 25 to 50 mg per day. Patients with major depressive disorder
typically show responses over the range of 100 to 300 mg per day, although response is
often seen in the range of 100 to 200 mg per day. Due to possible early activation of
anxiety symptoms, treatment of panic disorder is best started at a dose of 25 mg per day
for most patients, owing to increased sensitivity of side effects in this population. The
typical effective dose is usually 100 to 200 mg per day.
Paroxetine
•
Paroxetine HCl is available as 10-, 20-, 30-, and 40-mg-size tablets. The 20-mg-size tablets
are scored. Paroxetine CR is available in 12.5-, 25-, and 37.5-mg tablets. Paroxetine is also
available in an oral suspension at a concentration of 10 mg/5 mL. Paroxetine mesylate is
available as10-, 20-, 30-, and 40-mg tablets.
•
The recommended starting dose for paroxetine is 20 mg per day for all approved indications, except in
panic disorder, for which an initial dose of 10 mg per day is suggested. Starting paroxetine at 10 mg per
day is also suggested for the elderly, medically ill, or those with significant renal or hepatic impairment.
Paroxetine CR starting dose recommendations are similar, with 25 mg per day in major depressive
disorder and 12.5 mg per day in patients with panic disorder, the elderly, the medically ill, or those with
significant renal or hepatic impairment. Many clinicians find starting the more anxious or somatically
preoccupied patient at a dose of 10 mg of paroxetine or 12.5 mg of paroxetine CR for a few days to be of
benefit.
•
The target dose of paroxetine in the treatment of OCD is 40 mg per day, with most responders receiving 40 to 60 mg per
day. Presumably, doses of paroxetine CR need to be approximately 25 percent higher. The patient's response to treatment
of OCD is often slower than what is seen in major depressive disorder.
Patients with panic disorder usually tolerate the side effects of paroxetine, like antidepressants in general, if started at a
lower dose than is typically used in treating depression. Most panic disorder patients do better if started at an initial dose of
10 mg per day, with gradual titration to a target dose of 40 mg per day. Dose increases can be made at the rate of 10 mg per
week. The maximal dose studied in premarketing clinical trials of paroxetine was 60 mg per day. The dosing strategy with
paroxetine CR is similar, starting at 12.5 mg per week, and the maximal dose studied in clinical trials was 75 mg per day.
•
•
Dosing for other disorders is usually done with an initial dose of 10 to 20 mg per day (12.5 to 25.0 mg
per day for paroxetine CR) and a gradual upward titration. Paroxetine, like the other SSRIs, is well
tolerated over a wide dosing range.
Table 4: Side effects of SSRIs
Drug
Citalopram
Fluoxetine
Fluvoxamine
Paroxetine
Sertraline
Cardiotoxicty
?
_
_
_
Nausea
++
++
+++
++
++
Anticholinergic
effects
_
_
_
+
_
Sedation
_
_
+
++
+
Selective SerotoninNorepinephrine
Reuptake Inhibitors
(SNRI)
• The term serotonin-norepinephrine reuptake inhibitor
(SNRI) describes a group of medications that have
therapeutic effects that are presumably mediated by
concomitant blockade of neuronal serotonin (5-HT) and
norepinephrine uptake transporters.
•
The SNRIs are also sometimes referred to as dual reuptake inhibitors,
a broader functional class of antidepressant medications that
includes tricyclic antidepressants (TCAs) such as clomipramine and,
arguably, imipramine and amitriptyline.
• What distinguishes the SNRIs from TCAs is selectivity, which in this
context refers to a relative lack of affinity for other receptors,
especially muscarinic, histaminergic, and the families of α- and βadrenergic receptors. This distinction is an important one because
the SNRIs have a more favorable tolerability profile than the older
dual reuptake inhibitors.
•
•
•
•
There are currently three SNRIs approved for
use in the United States:
Venlafaxine (Effexor and Effexor XR),
desvenlafaxine succinate (Prestiq),
duloxetine (Cymbalta).
A fourth SNRI, milnacipran, is available in a number
of countries, including France and Japan.
Venlafaxine and Desvenlafaxine
• Venlafaxine and desvenlafaxine are bicyclic phenylethylamine
compounds that are structurally unrelated to other available
antidepressants and anxiolytics.
• First synthesized in the late 1970s, venlafaxine was found to block
uptake of 5-HT and norepinephrine in vitro, with a greater affinity
for the 5-HT transporter. Unlike the TCAs, venlafaxine was found
to have virtually no affinity for muscarinic, histaminergic, or α- or
β-adrenergic postsynaptic receptors.
•
Venlafaxine thus was predicted to exert antidepressant
activity comparable to the prototypic dual reuptake
inhibitors (i.e., amitriptyline and clomipramine), yet
affording a safety and tolerability profile that was more
similar to the SSRIs.
Pharmacology
• Venlafaxine and ODV inhibit neuronal uptake of 5-HT and, with
significantly lower in vitro affinity, norepinephrine. In addition to
a virtual lack of affinity for muscarinic, histamine 1 (H1), and
adrenergic receptors, neither the parent drug nor the metabolite
affect sodium fast channel activity. Venlafaxine and ODV do not
inhibit the activity of the monoamine oxidase isoenzymes
• Venlafaxine at higher doses also has been proposed to be
a triple reuptake inhibitor on the basis of in vitro work
documenting relatively weak inhibition of dopamine
reuptake; ODV probably shares this property.
• Venlafaxine and ODV are primarily eliminated by the kidneys. The
elimination half-lives of venlafaxine and its metabolite are short
(i.e., 4 and 10 hours, respectively).
Therapeutic Indications
• Venlafaxine is approved by the FDA for
treatment of four therapeutic disorders:
Major depressive disorder, generalized
anxiety disorder, social anxiety disorder,
and panic disorder.
• Major depressive disorder is currently
the only FDA-approved indication for
DVS.
Depression
•
•
•
The recommended starting dose of both formulations of venlafaxine, 75 mg per
day, is the minimum effective dose for treatment of depression. The IR formulation
is available in five doses (25-, 37.5-, 50-, 75-, and 100-mg tablets) and should be
administered with meals, on a two- or three-times-a-day basis. The XR
formulation is available in 37.5-, 75-, and 150-mg capsules. The bulky capsules
resulting from the microencapsulization process essentially precludes manufacture
of larger-dose capsules. The minimum therapeutic dose of DVS is 50 mg per day. At
the time of introduction, the drug will be available in 50- and 100-mg capsules.
Venlafaxine XR and DVS may be taken in the morning or evening, with or without
food, as clinically indicated.
In ambulatory clinical trials of venlafaxine using flexible doses, a modal daily dose
of 150 mg per day is typically observed, regardless of the formulation used.
When therapy at modest doses is ineffective, further increases up to 375 mg
per day can be considered, as tolerated. However, the maximum recommended
daily dose of the XR formulation is only 225 mg because of a lack of data on oncedaily ingestion of higher dosages
. Despite some concerns that noradrenergic activity may exacerbate anxiety,
efficacy has been established in studies of depressed people with significant
concomitant symptoms of anxiety.
Generalized Anxiety Disorder
• Venlafaxine XR received FDA approval for
treatment of generalized anxiety disorder
in 1999.
Social Anxiety Disorder
• The FDA approved venlafaxine for
treatment of social anxiety disorder
in early 2003
Other Psychiatric Disorders
•
•
•
There are numerous preliminary studies and case series pertaining to treatment
of various other mood and anxiety disorders, attention-deficit/hyperactivity
disorder (ADHD), and other psychiatric disorders. Premenstrual dysphoric
disorder may be thought of as a gender-specific form of brief recurrent
depression, and it is known to be responsive to SSRIs.
A randomized, double-blind, placebo-controlled study evaluated flexible doses
of venlafaxine therapy (range from 50 to 200 mg per day) across four menstrual
cycles among 157 women with premenstrual dysphoric disorder. There was
significantly greater improvement in the venlafaxine group compared to the
placebo group across measures of emotion, function, physical symptoms, and
pain.
As there is increasing evidence that 5-HT reuptake inhibitors are effective across
the full range of anxiety syndromes, it would not be surprising if other
indications were established for venlafaxine. With respect to panic disorder,
efficacy is being evaluated in several ongoing double-blind, placebo-controlled
studies. Despite the obvious parallels with clomipramine, the antiobsessional
effects of venlafaxine have not been extensively studied. Posttraumatic stress
disorder (PTSD) represents another area of potential applicability.
Tolerability
• Venlafaxine has a safety and tolerability
profile that approaches that of the more
widely prescribed SSRI class. For example, in
the pooled data set of Michael Thase and
colleagues, 9 percent of venlafaxine-treated
patients withdrew because of adverse
events, as compared to 7 percent of SSRItreated patients.
Hypertension
• Higher-dose venlafaxine therapy is associated
with an increased risk of sustained elevations of
blood pressure. Experience with the IR
formulation in studies of depressed patients
indicated that sustained hypertension was dose
related , increasing from 3 to 7 percent at
doses of 100 to 300 mg per day and to 13
percent at doses greater than 300 mg per day.
• When higher doses of the XR formulation are
used, however, monitoring of blood pressure is
recommended
Discontinuation Syndrome
•
Venlafaxine is one of the antidepressants most commonly associated with a
discontinuation syndrome
•
This syndrome is characterized by the appearance of a
constellation of adverse effects during a rapid taper or
abrupt cessation, including dizziness, dry mouth, insomnia,
nausea, nervousness, sweating, anorexia, diarrhea,
somnolence, and sensory disturbances.
•
As the XR formulation does not affect the elimination half-life of the
compound, it does not decrease the potential for discontinuation
symptoms.
• It is recommended that, whenever possible, a slow taper schedule
should be used when longer-term treatment must be stopped (e.g.,
reducing the daily dose by no more than 37.5 mg each
week).
• On occasion, substituting a few doses of the sustained-release
formulation of fluoxetine may help to bridge this transition.
Overdose
• There were no overdose fatalities in
premarketing trials, although electrocardiogram
(ECG) changes (e.g., prolongation of QT interval,
bundle branch block, QRS interval prolongation),
tachycardia, bradycardia, hypotension,
hypertension, coma, 5-HT syndrome, and
seizures were reported. Fatal overdoses have
been documented subsequently
• venlafaxine had a significantly greater fatal
toxicity index (a measure of overdose deaths per
million prescriptions) than the SSRIs
Duloxetine
• Duloxetine hydrochloride is a propanamine compound
that was synthesized in the 1980s by the same drug
discovery team that identified the SSRI fluoxetine .
• Like fluoxetine, duloxetine is a potent 5-HT uptake inhibitor
and lacks affinity for muscarinic, histaminic, and α- and βadrenergic receptors.
• Unlike fluoxetine, duloxetine is also a relatively potent
inhibitor of norepinephrine reuptake and in in vitro studies
duloxetine was found to be a substantially more potent
norepinephrine reuptake inhibitor than venlafaxine.
• Duloxetine was approved by the FDA for treatment of
major depressive disorder in 2004; other indications
include generalized anxiety disorder, fibromyalgia, and
management of neuropathic pain associated with
diabetic peripheral neuropathy.
Pharmacology
• Orally administered duloxetine is well absorbed, and
peak plasma levels are achieved approximately 3 hours
after ingestion. Duloxetine has no active metabolites
and exhibits linear pharmacokinetics within a dose
range of 20 to 120 mg. Steady-state concentrations are
achieved within 3 days of oral dosing, and the drug has
an elimination half-life of approximately 12 hours
• In the plasma, approximately 90 percent of the drug is
protein bound. After hepatic oxidation, metabolites of
duloxetine are primarily eliminated by the kidneys.
Duloxetine is a moderately potent inhibitor of the CYP
2D6 isoenzyme.
Tolerability
• The discontinuation rate due to adverse events in the studies
summarized by Charles Nemeroff and colleagues was 15 percent
in duloxetine-treated patients and 5 percent in
placebo-treated patients. Side effect attrition was slightly
higher in the duloxetine groups in the studies that used fluoxetine (10
vs. 6 percent) and paroxetine (14 vs. 10 percent) comparison groups,
although these differences were not statistically significant in
individual studies.
•
The most commonly reported side effects during duloxetine
therapy were nausea (22 percent), dry mouth (16 percent),
fatigue (11 percent), dizziness (11 percent), and somnolence (8
percent).
• Incidence of sexual dysfunction appears to be comparable to
that of the SSRIs. Of note, the incidence of nausea was similar
for duloxetine (dosed twice daily) to fluoxetine and paroxetine
(dosed every day) in head-to-head double-blind trials. Despite
the drug's potential usefulness for treatment of urinary
incontinence, urinary hesitancy and urinary retention were not
common occurrences in studies of depressed patients.
•
Duloxetine therapy resulted in a small increase in resting pulse rate
(approximately two beats per minute) and an average increase in blood pressure
of approximately 2 mm Hg in the studies reviewed by Nemeroff and colleagues
Milnacipran
• The SNRI milnacipran is available in Japan and several
European countries but, as of this time, is not being
considered for introduction in the United States.
• Milnacipran is distinguished as a dual reuptake inhibitor that (at least on
the basis of in vitro studies) may be viewed as the converse of
that of venlafaxine:
•
Specifically, milnacipran is approximately five times more potent for
inhibition of norepinephrine uptake than for 5-HT reuptake
inhibition.
• Milnacipran thus could be thought of as a relatively selective
norepinephrine uptake inhibitor at the minimum therapeutic dosage (50
mg per day) that exerts progressively greater inhibitory effects on 5-HT
reuptake at higher doses (i.e., 250 mg per day).
• Like the other SNRIs, milnacipran has virtually no affinity for muscarinic,
histaminic, or α- and β-noradrenergic receptors
Pharmacology
• Milnacipran has a half-life of approximately 8
hours and shows linear pharmacokinetics
between doses of 50 and 250 mg per day.
Metabolized in the liver, milnacipran has no
active metabolites. Milnacipran is primarily
excreted by the kidneys. Most orally administered
milnacipran is bioavailable, and only 13 percent
of milnacipran is bound to plasma protein.
Milnacipran is not thought to be a potent
inhibitor of any of the CYP isoenzymes, although
extensive studies have not been completed
Antidepressant Efficacy
• The countries that have approved milnacipran for general use as
an antidepressant have not required completion of a large
number of placebo-controlled studies, and, hence, efficacy is not
as well established, as is the case for venlafaxine or duloxetine
• Jean-Claude Bisserbe identified a number of RCTs contrasting
milnacipran with various TCAs. The novel SNRI was reported to be
as effective as imipramine, less effective than (at 50 mg per day) or
comparable to (at 200 mg per day) amitriptyline, and less effective
than (at 200 mg per day) or comparable to clomipramine. Three
published, controlled comparisons against SSRIs were identified, as
well as one relatively large, open-label comparison with
fluvoxamine. Results of these trials tended to favor
milnacipran for treatment of patients with more severe
depressive symptoms.
Tolerability
• In comparative clinical trials, milnacipran therapy
was associated with significantly fewer
anticholinergic and antihistaminic side effects
than the tertiary amine TCAs and fewer GI side
effects than the SSRIs. Noteworthy side effects
(i.e., incidence greater than an SSRI) included
dizziness, sweating, and urinary hesitancy.. Like
reuptake inhibitors, milnacipran should not be
prescribed in proximity to a MAOI.
Novel or Atypical Antidepressants
• Bupropion (NE and DA reuptake
inhibition??Dopamin increase)
• Trazodone (5 HT2 alpha-ANT)
• Nefazodone (Serzone)
• Mirtazapine (presynaptic alpha 2 ANT and 5 HT2
and 5 HT3 ANT)
Effects of atypical antidepressants on Reuptake
and 5-HT2
Amoxapine
Buproprion
Maprotiline
Mianserin
Nafazodone
Nomifensine
Trazodone
Venlafaxine
5-Ht reuptake
Noradrenaline
reuptake
5-HT2 antagonism
-/+
++
+
+
+
+
+
+
+
+
+
-
Side effects of atypical antidepressants
Drug
Mianserin
Mirtazepine
Nefazodone
Trazodone
Venlafaxine
Toxicity
+
+
Sedation
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+
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++
Hypotension
+
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-
Anticholinergic
effects
+
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+
Bupropion
• Originally introduced in the 1980s bupropion (Wellbutrin) has
become one of the more commonly prescribed antidepressants in
the United States.
• As a result of a unique pharmacology, bupropion is often used as
an alternative to selective serotonin reuptake inhibitors (SSRIs)
and serotonin norepinephrine reuptake inhibitors (SNRIs).
• In addition to its U.S. Food and Drug Administration (FDA)
approval in the treatment of depression, bupropion is also
approved for smoking cessation and is the only antidepressant to
receive FDA approval for the preventive treatment of seasonal
affective disorder (SAD)
• . Additionally, bupropion is used for numerous off-label
indications including the treatment of attentiondeficit/hyperactivity disorder (ADHD), sexual dysfunction, obesity,
and fatigue related to nonpsychiatric medical condition.
Dosing and Formulations
• Bupropion hydrochloride is available in IR, SR forms. As
of 2006, all of these formulations had become available
as generics in the United States.
• The usual starting dose in all formulations is 150 mg
per day taken in the morning, but the IR form was
often started at 100 mg twice a day. The average
therapeutic dose of bupropion for the treatment of
depression is 300 to 450 mg per day.
• In smoking cessation, bupropion SR is typically started
at 150 mg per day and then increased to the target
dose of 300 mg per day.
Side Effects
•
The pharmacodynamics effects of bupropion result in a side effect profile different from
most antidepressants. Many of the adverse events reported with bupropion are associated
with its noradrenergic, and to a lesser extent, dopaminergic effects.
• Insomnia is one of the common side effects of bupropion, affecting at
least 11 percent of patients in clinical trials.
•
Anxiety and agitation may occur as treatment emergent effects.
•
At least 6 percent of patients in clinical trials also experienced a mild to moderate tremor.
•
Treatment emergent psychotic symptoms have rarely been reported in depressed
patients
• Analysis of data sets revealed an enhanced risk of seizure in patients
with a history of eating disorders, head trauma, or previous seizure
disorder. Also, doses above 450 mg per day or 200 mg at one time (for
the IR formulation) enhanced the risk of seizure. For extended release
formulations at doses of 450 mg per day or less, the seizure risk is
estimated at 0.1 to 0.2 percent, which is comparable to the rates
reported with SSRIs and may be less than the rates reported with some
TCAs and maprotiline (Novo-Maprotiline).
Side Effects
•
Other common side effects reported in trials included nausea, dry mouth,
excessive sweating, tinnitus, and rash. The most common reasons patients
discontinued bupropion in acute clinical trials in depression were nausea and
rash.
•
•
Bupropion has a favorable cardiovascular profile with few cardiac effects.
Bupropion is not known to have clinically significant effects on blood pressure, heart rate,
or cardiac conduction. Thus, bupropion is commonly used in patients with known cardiac
pathology. However, there have been rare reports of significant hypertension associated
with bupropion in patients with and without a preexisting history of high blood pressure.
Side effects common to many antidepressants (including sexual side effects and weight
gain) appear uncommon with bupropion.
•
•
•
As noted earlier, bupropion has been associated with weight loss, and there are
many reports of improved sexual functioning, including increased libido and
arousal, with the drug.
Other side effects such as hepatoxicity, hematopoietic changes, and severe
headaches occur rarely in bupropion-treated patients. Thus, the side-effect
profile makes bupropion an important alternative to many patients who cannot
tolerate other antidepressants.
Trazodone
History
• Trazodone was first marketed in Europe in the 1970s
and received U.S. Food and Drug Administration (FDA)
approval in 1981 for the treatment of major depression
in the United States.
• Its improved safety and tolerability compared to TCAs
was most likely responsible for trazodone's rapid rise in
clinical use after its introduction.
• However, with the increased popularity of selective
serotonin reuptake inhibitor (SSRI) antidepressants,
trazodone has fallen out of favor as a first-line
treatment for depression in the United States.
Pharmacology
Pharmacokinetics
• Trazodone is absorbed efficiently by the human
digestive tract after oral administration,
reaching peak plasma concentration in about 1
hour.
• When consumed with food, the total amount of
drug absorption is increased, maximum plasma
concentration is decreased, and time to peak
concentration is doubled. Since some adverse
effects such as dizziness are related to peak
plasma levels, this strategy has been shown to
increase tolerability.
Effects on Specific Organs and Systems
• In both premarketing trials and postmarketing
surveillance, the adverse effects seen with trazodone
therapy have generally been benign,
• mostly limited to dry mouth, headache, nausea,
drowsiness, fatigue, and dizziness, the latter in part
secondary to orthostatic hypotension.
• Unlike TCAs, trazodone is virtually devoid of
anticholinergic side effects, including major cardiac
conduction abnormalities, thus explaining its benign
profile following overdose.
• The adverse reaction for which trazodone is most
widely recognized, although infrequent, is priapism
Insomnia
• In recent years, it has become a common practice for
clinicians to utilize trazodone for the treatment of
primary insomnia, depression-related insomnia, and
insomnia experienced as an adverse effect of
antidepressant treatment.
• This practice is due to trazodone's sedating side-effect
profile that is generally more favorable than that of
benzodiazepine hypnotic agents.
• The dosage can be easily titrated by patients to
achieve an optimal balance between reducing sleep
latency and nocturnal awakenings and minimizing
next morning grogginess.
Dosage and Administration
•
•
•
•
•
The manufacturer's package insert recommends initiating trazodone at 150
mg per day in divided doses, increasing by 50 mg per day in intervals of 3 to
4 days up to a maximum dose of 400 mg per day in outpatients and 600 mg
per day in inpatients.
Taking these considerations into account, the authors suggest initiating
trazodone at 100 mg once daily at bedtime. A dosage increase of 50 mg per
day in 4- to 7-day intervals, depending on sensitivity to side effects, will
allow patients to achieve the therapeutic range of 150 to 300 mg within 2 to
4 weeks. As some patients may require higher doses for maximal benefit,
further dose increases up to the maximum of 600 mg per day may be tried if
partial efficacy is observed at lower doses.
Note that these recommendations are limited to adults, as trazodone has
not been tested in children.
For the treatment of primary or medication-related insomnia, doses in the
50- to 100-mg range are usually sufficient.
Trazodone is available in scored 50- and 100-mg tablets and in 150- and 300mg tablets that can be divided into halves or thirds for convenient dosing
adjustment and administration.
Nefazodone
• Structurally related to trazodone but does
not has the sedative effect and does not
block α- adrenoceptors , however; it likes
most SSRI inhibit P450 3A4 isoenzyme.
Mirtazapine
• Mirtazapine (Remeron) is a tetracyclic
piperazinoazepine compound that was
approved by the U.S. Food and Drug
Administration (FDA) in 1995 for treatment of
depression.
• Unlike most newer antidepressants,
mirtazapine has virtually no effect on
monoamine uptake.
α2 – adrenoceptors antagonists
• Rather, therapeutic effects are thought to be
mediated by inhibition of α2-adrenergic
receptors and blockade of postsynaptic
serotonin type 2 (5-HT2) and type 3 (5-HT3)
receptors.
• First synthesized in the early 1980s,
mirtazapine is related to one older
antidepressant, mianserin (Tolvon).
Pharmacology
• Mirtazapine has a half-life of approximately 30
hours and reaches steady state after 6 days of
therapy.
• Linear pharmacokinetics are observed across the
therapeutic dose range (i.e., 15 to 60 mg per
day).
• Mirtazapine is essentially completely absorbed after
oral dosing, and food has little effect on the rate or
extent of absorption. Approximately 85 percent of
circulating drug is bound to plasma protein.
Other Indications for Mirtazapine
• Mirtazapine is not formally indicated for
treatment of any other disorder. Nevertheless,
mirtazapine may be useful the treatment of
insomnia, panic disorder, generalized anxiety
disorder, posttraumatic stress disorder (PTSD),
and obsessive-compulsive disorder (OCD), as
well as autism and other pervasive
developmental disorders.
• A number of small studies and case series have
evaluated the utility of mirtazapine in treating
anxiety and depression in cancer patients.
• The most common side effects reported
during mirtazapine therapy are sedation,
increased appetite, weight gain, and dry
mouth.
• When compared to SSRIs or SNRIs,
mirtazapine therapy is associated with
significantly lower rates of gastrointestinal
disturbance and a lower incidence of
treatment-emergent sexual dysfunction.
ALIREZA HAJ SEYED JAVADI MD.
PSYCHIATRIST
ALIREZA HAJ SEYED JAVADI MD.
PSYCHIATRIST