CHAPTER 30: ANTIDEPRESSANT AGENTS therapies increase neurogenesis and synaptic

pp. 510-528 connectivity in cortical areas such as the hippocampus

Major depressive disorder (MDD)
- characterized by depressed mood most of the
time for at least 2 weeks and/ or loss of interest or
pleasure in most activities
- characterized by disturbances in sleep and
appetite as well as deficits in cognition and energy
-may considerably worsen the prognosis for
patients with a variety of comorbid medical conditions.
- Coronary artery disease, diabetes, and stroke
appear to be more common
-prolongs illness (drop in volume of
hippocampus)
- Decrease in BDNF and monoamines
Antidepressants- increase BDNF levels with chronic use
-reduce glutaminergic transmission
-According to FDA, can be used in tx:
-Primary use: tx MDD
-panic disorder
-generalized anxiety disorder (GAD)
-posttraumatic stress disorder (PTSD)
-obsessive-compulsive disorder (OCD)
-in pain: neuropathic pain and the pain
associated with fibromyalgia
-premenstrual dysphoric disorder (PMDD)
-mitigating the vasomotor symptoms of
menopause
-treating stress urinary incontinence
-activation of tyrosine kinase receptor B in both
neurons and glia = neuronal survival and growth effects
-drop in BDNF levels = stress and pain
= this loss of neurotrophic support
contributes to atrophic structural changes in the
hippocampus and perhaps other areas such as the
medial frontal cortex and anterior cingulate
-electroconvulsive therapy, also appear to robustly
stimulate BDNF levels and hippocampus neurogenesis
Hippocampus - important both in contextual memory
and regulation of the hypothalamic-pituitary-adrenal
(HPA) axis
Anterior cingulate - plays a role in the integration of
emotional stimuli and attention functions
Medial orbital frontal cortex
- play a role in memory, learning, and emotion
MDD= 5-10% loss in the volume of hippocampus
Depression and chronic stress states= substantial loss of
volume in the anterior cingulate and medial orbital
frontal cortex

Pathophysiology of Major Depression

1. Monoamine hypothesis- older idea that a deficit in
function or amount of monoamines is central to the
biology of depression
2. Neurotrophic hypothesis
(3.) Neuroendocrine factors

Neurotrophic Hypothesis

Brain-derived neurotrophic factor (BDNF)

-increase in BDNF levels = antidepressant
activity
-polymorphisms of this may not exhibit
antidepressant effects
-nerve growth factor
-critical in the regulation of neural plasticity,
resilience, and neurogenesis
-depression is associated with the loss of
neurotrophic support and that effective antidepressant
FIGURE 301 The neurotrophic hypothesis of major
depression. Changes in trophic factors (especially brain-
derived neurotrophic factor, BDNF) and hormones appear to
play a major role in the development of major depression ( A)
. Successful treatment results in changes in these factors ( B) .
CREB, cAMP response element-binding (protein). BDNF,
brain-derived neurotrophic factor.
Monoamines & Other Neurotransmitters
FIGURE 302 The amine 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. AC, adenylyl cyclase; 5-HT,
serotonin; CREB, cAMP response element-binding (protein);
DAG, diacyl glycerol; IP 3, inositol trisphosphate; MAO,
monoamine oxidase; NET, norepinephrine transporter; PKC,
protein kinase C; PLC, phospholipase C; SERT, serotonin
transporter
Monoamine hypothesis
- Suggests that depression is related to a deficiency in
the amount or function of cortical and limbic serotonin
(5-HT), Norepinephrine (NE), and dopamine (DA)
- Evidence to support the monoamine hypothesis comes
from several sources:
*(Noradrenergic part)
- It has been known for many years that
reserpine treatment, which is known to deplete
monoamines, is associated with depression in a subset
of patients
- desipramine- noradrenergic antidepressant
that exhibits no relapse with tryptophan-free diet
- depleting catecholamines in depressed
patients who have previously responded to
noradrenergic agents likewise tends to be associated
with relapse
-patients who responded to NE antidepressant
+ NE inhibitor = return of depression
*(Serotonergic part)
- Similarly, depressed patients who respond to
serotonergic antidepressants such as fluoxetine often
rapidly suffer relapse when given diets free of
tryptophan, a precursor of serotonin synthesis
* Finally, perhaps the most convincing line of evidence
supporting the monoamine hypothesis is the fact that
all available antidepressants appear to have significant
effects on the monoamine system
*Increase glutamate in CSF and decrease in plasma =
depression
-stress increases release of glutamate but is
inhibited by antidepressants
-Ketamine- antidepressant in the glutamate
system
-potent, high-affinity, noncompetitive
NMDA receptor antagonist has long been used for
anesthesia and demonstrated rapid antidepressant
effects
Neuroendocrine Factors in the Pathophysiology of
Depression
-Depression is known to be associated with a number of
hormonal abnormalities
-abnormalities in the HPA axis in patients with
MDD
HPA abnormalities (MDD)- associated with elevated
cortisol levels, nonsuppression of adrenocorticotropic
hormone (ACTH) release, chronically elevated levels of
corticotropin-releasing hormone
- indicate a dysregulation of the stress hormone axis.
- psychotic depression and milder MDD
* Thyroid dysregulation has also been reported in
depressed patients.
- blunting of response of thyrotropin to
thyrotropin-releasing hormone, and elevations in
circulating thyroxine during depressed states
* Sex steroids
-Estrogen deficiency states, which occur in the
postpartum and postmenopausal periods
-testosterone deficiency in men is sometimes
associated with depressive symptoms
- Hormone replacement therapy in hypogonadal men
and women may be associated with an improvement in
mood and depressive symptoms
Integration of Hypotheses Regarding the
Pathophysiology of Depression
Parang summary ng tatlo:
HPA and steroid abnormalities may contribute to
suppression of transcription of the BDNF gene.
Glucocorticoid receptors are found in high density in
the hippocampus. Binding of these hippocampal
glucocorticoid receptors by cortisol during chronic
stress states such as major depression may decrease
BDNF synthesis and may result in volume loss in stress-
sensitive regions such as the hippocampus. The chronic
activation of monoamine receptors by antidepressants
appears to have the opposite effect of stress and results
in an increase in BDNF transcription. In addition,
activation of monoamine receptors appears to down-
regulate the HPA axis and may normalize HPA function.
- weaknesses of the monoamine hypothesis
- amine levels increase immediately with
antidepressant use, but maximum beneficial effects of
antidepressants are not seen for many weeks
- The time required to synthesize neurotrophic factors
has been proposed as an explanation for this delay of
antidepressant effects
- Appreciable protein synthesis of products such as
BDNF typically takes 2 weeks or longer and coincides
with the clinical course of antidepressant treatment.
BASIC PHARMACOLOGY OF ANTIDEPRESSANTS
A. Selective Serotonin Reuptake Inhibitors
SSRI- used in MDD, GAD, PTSD, OCD, panic disorder,
PMDD, and bulimia
- first drug: Fluoxetine (active metabolite,
norfluoxetine)
-high affinity for monoamines but
lacked the affinity for histamine, acetylcholine, and
adrenoceptors
- most commonly prescribed antidepressant
(eg, Fluoxetine, sertraline, and citalopram exist as
isomers and are formulated in the racemic forms;
paroxetine and fluvoxamine are not optically active.
Escitalopram is the S enantiomer of citalopram)
- highly lipophilic, cheap, ease of use, safety in
overdose, relative tolerability, and broad spectrum of
use
B. Serotonin-Norepinephrine Reuptake Inhibitors
1. SNRIs bind to SERT and NET ONLY!
- Treatment of MDD, pain disorders including
neuropathy and fibromyalgia, generalized anxiety,
stress urinary incontinence, and vasomotor symptoms
of menopause.
-Venlafaxine - bicyclic compounds
- discovered in the process of evaluating
chemicals that inhibit binding of imipramine
-similar to imipramine but with more favorable
adverse-effect profile
-Desvenlafaxine metabolite of venlafaxine; bicyclic
compounds
-Duloxetine- three-ring structure unrelated to the TCAs
-Levomilnacipran active metabolite of the racemic
SNRI, milnacipran
-Milnacipran - treatment of fibromyalgia(USA);
treatment of depression (Europe)
2. Tricyclic Antidepressants
- are used primarily in depression that is unresponsive
to more commonly used antidepressants such as the
SSRIs or SNRIs
- relatively poorer tolerability compared with newer
agents, to difficulty of use, and to lethality in overdose
-treatment of pain conditions, enuresis, and insomnia
- Nine TCAs (Imipramine, desipramine, clomipramine,
trimipramine, amitriptyline, nortriptyline, doxepin, and
protryptyline) are available in the USA, and they all have
an iminodibenzyl (tricyclic) core (like carbamazepine)
-Imipramine- prototype TCA
- highly anticholinergic and is a relatively strong
serotonin as well as norepinephrine reuptake inhibitor
-Desipramine- more potent and somewhat more
selective norepinephrine reuptake inhibitor than is
imipramine
*they differ by only a methyl group in the propylamine
side chain
C. 5-HT 2 Antagonists
-Trazodone triazolo moiety is thought to impart
antidepressant effects
-primary metabolite: m-chlorphenylpiperazine
(m-cpp), is a potent 5-HT2 antagonist
-use: unlabeled hypnotic (highly sedating and
not associated with tolerance or dependence)
-Nefazodone chemically related to trazodone
- primary metabolites: hydroxynefazodone and
m-cpp are both inhibitors of the 5-HT2 receptor
 - FDA black box warning: hepatotoxicity
(hepatic failure)
*both treat MDD and anxiety disorders
-Vortioxetine newer agent that acts as antagonist of
the 5-HT3, 5-HT7, and 5-HT1D receptors, a partial agonist
of the 5-HT1B receptor, and an agonist of the 5-HT1A
receptor.
-inhibits serotonin transporter not related to
SERT (so not = to SSRI)
D. Tetracyclic and Unicyclic Antidepressants
-primary use is in MDD that is unresponsive to other
agents.
- bupropion, mirtazapine, amoxapine, vilazodone, and
maprotiline
-Bupropion unicyclic aminoketone
- somewhat resembles amphetamine in the
structure and, like the stimulant, has CNS activating
properties
- has different side-effects than most
antidepressants
-not associated with sexual effects
-Mirtazapine not commonly associated with sexual
effects
-tetracyclic = piperazino-azepine group
-mirtazapine, amoxapine, maprotiline
-tetracyclic
-Amoxapine N-methylated metabolite of loxapine (an
older antipsychotic drug)
-Amoxapine and Maprotiline - share structural
similarities and side effects comparable to the TCAs
-Vilazodone has multi-ring structure that allows it to
bind potently to the serotonin transporter but
minimally to the dopamine and NE transporter
E. Monoamine Oxidase Inhibitors
-first modern class of antidepressant
-now rarely used in clinical practice because of toxicity
and potentially lethal food and drug interactions
-treatment of depression unresponsive to other
antidepressants
-historically to treat anxiety states, including social
anxiety and panic disorder
-Selegiline is used for the treatment of Parkinsons
disease
-Current MAOIs: hydrazine derivatives (phenelzine and
isocarboxazid) and non-hydrazine derivatives
(tranylcypromine, selegiline, and moclobemide)
*The hydrazines and tranylcypromine bind irreversibly
and nonselectively with MAO-A and -B, whereas other
MAOIs may have more selective or reversible properties
-Tanylcypromine- resembles amphetamine in chemical
structure
-Selegiline resembles amphetine-like metabolites
*as a result MAOIs are substantial CNS stimulants
PHARMACOKINETICS (TABLE 30-1)
A. Selective Serotonin Reuptake Inhibitors
-fluoxetine active metabolite, norfluoxetine (may
have greater plasma concentrations)
- norfluoxetine longest t1/2 of all SSRIs
- 3x longer elimination t1/2 than parent
-and paroxetine are potent inhibitors of
CYP2D6 isoenzyme = potential drug interactions
-fluvoxamine inhibitor of CYP3A4
-Citalopram, Escitalopram, and Sertraline
- have modest CYP interactions
B. Serotonin-Norepinephrine Reuptake Inhibitors
1. Selective SNRI
-Venlafaxine and active metabolite Desvenlafaxine
-t1/2 =8-11hrs; once a day
- lowest protein bound of all (27-30%
-Metabolized by CYP2D6
-Duloxetine well absorbed; t1/2= 12-15hrs; once a day
-Highly protein bound (97%)
-metabolized by CYP2D6 and CYP1A2
-Milnacipran and Levomilnacipran
-well absorbed; with shorter t1/2; low protein
binding
-largely excreted unchanged in the urine
-Levomilnacipran undergoes desethylation via
3A3/4
2. Tricyclic Antidepressant
-well absorbed with long half-lives; once daily
-undergo demethylation, aromatic hydroxylation, and
glucuronide conjugation
* he secondary amine TCAs, including desipramine and
nortriptyline, lack active metabolites and have fairly
linear kinetics. These TCAs have a wide therapeutic
window, and serum levels are reliable in predicting
response and toxicity.
C. 5-HT Receptor Modulators
-Trazodone and Nefazodone
-rapidly absorbed and undergo extensive
hepatic metabolism
-low bioavailabilty and protein binding
-short t1/2
* Trazodone is often prescribed as a single dose at night
as a hypnotic in lower doses than are used in the
treatment of depression
*Nefazodone inhibit CYP3A4 system
*Vortioxetine is not a potent inhibitor of CYP
isoenzymes;extensively metabolized by CYP2D6

D. Tetracyclic and Unicyclic Agents

-Bupropion highly protein bound (85%)

- undergoes hepatic metabolism
-biphasic: first phase= 1 hour and second phase
= 14hrs
-Amoxapine highly protein bound (85%)
-7-hydroxyamoxapamine potent D2 blocker;
antipsychotic effects
-Mirtazapine- demethylated followed by hydroxylation
and glucuronide conjugation
- t1/2 = 20-40hrs
- Vilazodone t1/2 = 25 hrs

E. Monoamine Oxidase Inhibitors

*metabolized via different pathways but tend to have
extensive first-pass effects that may substantially
decrease bioavailability.
-well absorbed in the GIT
-Phenelzine acetylation
-Tranylcypromine- ring hydroxylated and N-Acetylated
-Selegiline- N-demethylated
-TRANDERMAL AND sublingual

PHARMACODYNAMICS