Download Drugs for Depressive Disorders

Drugs for Depressive Disorders
Kaukab Azim, MBBS, PhD
Drug List
Antidepressants
MAO inhibitors
Tricyclics
Atypicals
Imipramine
Amitriptamine
Clomipramine
Trazodone
Bupropion
Phenelzine
Mirtazapine
Non Selective Selective
* This drug will be covered in another lecture
Selegiline*
SSRIs
SNRIs
Fluoxetine
Paroxetine
Sertraline
Citalopram
Venlafaxine
Classification of Depressive Disorders
(from DSM IV text revision)
Type
Major depressive disorder
(endogenous depression – about 20% of all
depressions)
Dysthymic disorder
Features
Depression is autonomous and is
unresponsive to changes in life. Biological
factors seem important (family history).
It can occur as a single episodeor may be
recurrent.
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
Depressive disorder not otherwise specified are
 Minor depressive disorder
 Recurrent brief depressive disorder
The Monoamine Hypothesis of
Depression
➼ This hypothesis suggests that depression is related to a deficiency in
the amount or function of cortical and limbic serotonin and
norepinephrine.
➼ Evidence for this hypothesis includes the following:
1.
Reserpine, which depletes monoamine stores in the CNS, is
associated with depression in subset of patients.
2.
There is an elevation of MAO-A in most brain regions of depressed
patients.
3.
Genetic studies indicate a functional polymorphism for the gene of
serotonin transporter. Subjects who are homozygous for the s (short)
allele may be more vulnerable to developing major depression in
response to stress.
4.
All available antidepressants appear to increase the levels of NE
and/or 5-HT in the synaptic cleft.
The Dysregulation Hypothesis of
Depression
➼This hypothesis suggests that depression is related to a
failure of homeostatic regulation of neurotransmitter
systems.
➼Evidence for this hypothesis includes the following:
1.
Chronic (but not acute) administration of most
antidepressants causes a down-regulation of postsynaptic CNS
receptors (mainly beta-adrenergic and serotonergic).
2.
Non pharmacological therapies of depression (like
electroconvulsive therapy and REM sleep deprivation) cause a
similar down-regulation of postsynaptic CNS receptors.
The Neuroendocrine Hypothesis of
Depression
Evidence for this hypothesis includes the following:
1.
2.
3.
4.
5.
6.
7.
There is substantial evidence that nerve growth factors such as brain
derived neurotrophic factor (BDNF) are critical in the regulation of
neural plasticity and neurogenesis.
There is a reduction of BDNF associated with stress and pain.
BDNF directly infused into lateral ventricle of animals shows
antidepressant effects.
Depression and chronic stress states are associated with a substantial
loss of volume in anterior cingulate and medial orbital frontal cortex.
Major depression is associated with a 5-10% loss of volume in the
hippocampus.
Chronic (but not acute) administration of all antidepressants increases
BDNF and is associated with an increased neurogenesis in the
hippocampus.
ECT therapy and 24 hour sleep deprivation stimulate BDNF levels and
hippocampus neurogenesis in animal models.
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 heterocyclic) antidepressants (HEADS)
Mechanisms are often unclear (see specific agents below) 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
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 (see table in next slide).
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 5HT2-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, 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, pharmacological
and cognitive behavioral therapy are recommended
with close supervision.
Adverse effects of
tricyclic antidepressants
CNS effects
➼ Drowsiness (the most common CNS effect), sedation, lassitude,
fatigue, dysphoria, dizziness
➼ Tremor, paresthesias, seizures (tricyclics lower the seizure threshold)
➼ Pseudoparkinsonism (rare)
Autonomic effects
➼ Anticholinergic effects (memory impairment, xerostomia, blurred
vision, constipation, urinary retention)
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 isunknown
➼Sexual dysfunction
➼SIADH secretion (rare)
Overdosage
➼Tricyclics have a narrow therapeutic index.
Manifestations include agitation, delirium,
hyperpyrexia, convusions, 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 (the highest rates of all the
antidepressants).
➼Dangerous interactions with certain foods and with
serotonergic drugs.
➼Hypertensive crisis (see interactions below); is rare but can
be lethal.
Adverse effects of
SSRIs and SNRIs
GI effects
➼ 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 (tremor, akathisia, dystonias) (rare) (serotonin
and dopamine appear to have an inverse relationship in certain areas of
the brain, whereby central stimulation of 5-HT receptors result in inhibition
of dopaminergic transmission).
Adverse effects of
SSRIs and SNRIs
Other adverse effects
➼ Weight gain (mechanism unknown)
➼ SIADH (rare)
➼ Serotonin syndrome (see below)
➼ SSRI (mainly fluoxetine and paroxetine) are inhibitors of the
cytochrome P450 system and therefore can increase the effects of
several drugs given concomitantly (see interactions below).
➼ 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
➼ Serotonergic pathways from the raphe nuclei project upward and inhibit the mesolimbic dopamine
system. This inhibition likely mediates the decreased libido anorgasmia.
➼ Serotonergic pathways from the raphe nuclei project downward to the spinal cord and likely inhibit
the mechanistic aspects of sexual function (erection, ejaculation, vaginal lubrication, clitoral
congestion)
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
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
Etiology
A large number of medications either alone or in combination can
produce the serotonin syndrome, when given in high doses. These
include antidepressants, opioids, psychostimulants, triptans,
psychedelics, herbs (St. John’s wort, ginseng, nutmeg). The
combination of two drugs that enhance serotonin transmission (i.e.
SSRIs/SNRIs with MAO inhibitors or with tricyclics antidepressants)
can be particularly dangerous.
Pathophysiology
Overstimulation of 5-HT1A receptors (and perhaps of 5-HT2
receptors) appears to contribute substantially to the condition.
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 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 doses.
➼ Therefore many clinicians select an antidepressant by matching the
patient’s presenting symptoms to the adverse effect profile of
antidepressant medications.
➼ 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.