Antidepressant drugs

 Drugs that are used to relieve or prevent
psychic depression.
 Work by altering the way in which specific
chemicals, called neurotransmitters, work
in our brains (i.e. in the case of
depression, some of the neurotransmitter
systems don’t seem to be working
properly).
 They increase the activity of these
chemicals in our brains

 The precise cause of affective disorders
remains elusive.
 Evidence implicates alterations in the
firing patterns of a subset of biogenic
amines in the CNS, Norepinephrine (NE)
and Serotonin (5-HT).
 Activity of NE and 5 -HT systems?.

 1950: Reserpine  Induce depression
 Study: Reserpine depletes storage or amine
neurotransmitters such as serotonin and
norepinephrine
 Break-through: MAOI and TCA
 Then: Depression  Amine-dependent
synaptic transmission
(Antidepressants  Amine by means of
reuptake and metabolism)
 Conclusion: Major model for the subsequent
antidepressants, except Buproprion.

MAO
COMT
Amine neurotransmitters are
either degraded (metab)
or reuptaken
Mito

Almost all NE pathways in the brain originate from the
cell bodies of neuronal cells in the locus coereleus in
the midbrain, which send their axons diffusely to the
cortex, cerebellum and limbic areas (hippocampus,
amygdala, hypothalamus, thalamus).
 Mood: -- higher functions performed by the cortex.
 Cognitive function: -- function of cortex.
 Drive and motivation: -- function of brainstem
 Memory and emotion: -- function of the hippocampus
and amygdala.
 Endocrine response: -- function of hypothalamus.
 and  receptors.

A synapse that uses norepinephrine (NE)

Reuptake of NE
Monoamine oxidase, located on outer membrane
of mitochondria; deaminates catecholamines free in
nerve terminal that are not protected by vesicles
Selective inhibitor,
reboxetine
Cocaine blocks the NET
Antidepressant
MAO Inhibitors
Stimulant

PO4
Cl-
Cl-
GABA
Cl-
Cl- Cl- Cl- Cl- Cl-
GABA
Out
In

Why does a small amount of stress help you learn better?
But, too much chronic, severe stress 
DEPRESSION

As with the NE system, serotonin neurons
located in the pons and midbrain (in groups
known as raphe nuclei) send their projections
diffusely to the cortex, hippocampus,
amygdala, hypothalamus, thalamus, etc. --
same areas implicated in depression. This
system is also involve in:
• Anxiety.
• Sleep.
• Sexual behavior.
• Rhythms (Suprachiasmatic nucleus).
• Temperature regulation.
• CSF production.

 Major depression
 Chronic depression (Dysthymia)
 Atypical depression
 Bipolar disorder/Manic
depression
 Seasonal depression (SAD)

 Major depression – recurring and disabling.
Symptoms must last for at least two weeks
and impair one’s ability to interfere with a
person's ability to work, sleep, study, eat,
and enjoy once-pleasurable activities.
 Chronic depression – less disabling than
major depression, but symptoms can last
longer, sometimes being unhappy for two
years. More common in women, affects 11
million people.
 Atypical depression, rather than the other
two, is characterized less by pervasive
sadness and more by overeating,
oversleeping, sensitivty to rejection

 Bipolar/manic depression oscillates between
major depression and epsidoes of mania
(extreme elation), Bipolar I – episode of
mania with or without depression. Bipolar II –
episode of depression with episode of
hypomania or mania.
 Seasonal depression (SAD) – often occurs
where winters are short or there is a big
change in the amount of sunlgiht, and often
treated with light therapy.

 persistently sad, anxious, or empty moods
 loss of pleasure in usual activities (anhedonia)
 feelings of helplessness, guilt, or worthlessness
 crying, hopelessness, or persistent pessimism
 fatigue or decreased energy
 loss of memory, concentration, or decision-making capability
 restlessness, irritability
 sleep disturbances
 change in appetite or weight
 physical symptoms that defy diagnosis and do not respond to
treatment (especially pain and gastrointestinal complaints)
 thoughts of suicide or death, or suicide attempts
 poor self-image or self-esteem (as illustrated, for example, by
verbal self-reproach)

 Extensive patient and family history
 Blood test for hypothyroidism
 Current medication
 DSM-IV
 One of the first two symptoms
 FOUR other symptoms

 Genetics
 Death/Abuse
 Medications

 Psychotherapy
 Electroconvulsive therapy
 Natural alternatives
Medication
SSRIs
MAOIs
TCAs
SNRIs
NDRIs
TeCAs

 MAO catalyze deamination of intracellular
monoamines
 MAO-A oxidizes epinephrine, norepinephrine,
serotonin
 MAO-B oxidizes phenylethylamine
 Both oxidize dopamine nonpreferentially

 History
 Isoniazid
 Iproniazid
 Current Drugs
 Mechanism of Action
 Side Effects
Isoniazid
Iproniazid

 MAO Inhibitors (nonselective)
 Phenelzine (Nardil)
 Tranylcypromine (Parnate)
 Isocarboxazid (Marplan)
 MAO-B Inhibitors (selective for MAO-B)
 Selegiline (Emsam)

 MAO contains a
cysteinyl-linked
flavin
 MAOIs covalently
bind to N-5 of
the flavin residue
of the enzyme

 Drowsiness/Fatigue
 Constipation
 Nausea
 Diarrhea
 Dizziness
 Lightheadedness,
 Decreased urine
output
 Decreased sexual
function
 Sleep disturbances
 Muscle twitching
 Weight gain
 Blurred vision
 Headache
 Increased appetite
 Restlessness
 Shakiness
 Weakness
 Increased sweating

 Side effects have put MAOIs in the second or
third line of defense despite superior efficacy
 MAO-A inhibitors interfere with breakdown of
tyramine
 High tyramine levels cause hypertensive crisis (the
“cheese effect”)
 Can be controlled with restricted diet
 MAOIs interact with certain drugs
 Serotonin syndrome (muscle rigidity, fever,
seizures)
 Pain medications and SSRIs must be avoided

 History
 Imipramine
 Current Drugs
 Side Effects
Imipramine

 Imipramine was first tried as an
antipsychoti drug for schizophrenia,
proved to be insufficient but proved to
have antidepressant qualities, in the 50s
around the same time as MAOIs.
 Imipramine is very good for severe
depression, but it’s almost too good – also
causes hypomania and mania

 Amitriptyline
 Desipramine (Norpramin)
 Doxepin (Sinequan)
 Imipramine (Tofranil, Tofranil-PM)
 Nortriptyline (Pamelor)
 Protriptyline (Vivactil)
 Trimipramine (Surmontil)

 Side effects have made them second line of
defense to SSRIs but they are good for treatment
resistant depression bc they are so strong.
 Amitriptyline – most widely used, most effectve
 Desipramine – active metabolite of imipramine,
used for neuropathic pain
 Doxepin – used for depression and insomnia
 Imipramine – used for major depression and
enuresis
 Nortriptyline – same thing
 Protriptyline – depression UNIQUE BECAUSE IT IS
ENERGIZING rather than sedating
 Trimipramine – depression, insomnia, and pain

 TCAs inhibit serotonin,
norepinephrine, and
dopamine transporters,
slowing reuptake
 TCAs also allow for the
downregulation of post-
synaptic receptors
 All TCAs and SSRIs contain an
essential amino group that
appears to interact with Asp-
98 in hSERT

 Muscarinic M1 receptor antagonism - anticholinergic
effects including dry mouth, blurred vision,
constipation, urinary retention and impotence
 Histamine H1 receptor antagonism - sedation and
weight gain
 Adrenergic α receptor antagonism - postural
hypotension
 Direct membrane effects - reduced seizure threshold,
arrhythmia
 Serotonin 5-HT2 receptor antagonism - weight gain
(and reduced anxiety)

 Nonselectivity results in greater side effects
 TCAs can also lead to cardiotoxicity
 Increased LDH leakage
 Slow cardiac conduction
 High potency can lead to mania
 Contraindicated with persons with bipolar disorder
or manic depression

 Current Drugs
 Mirtazapine (Remeron)
 Same as TCAs
 Side Effects

 Most commonly prescribed class
 Current drugs
 Mechanism of action
 Side effects
Serotonin

 Also first rationally designed drug class,
up until the 70s the antidepressants were
sort of found by accident
 Serotonin is also referred to as 5-
hydroxytryptamine

 citalopram (Celexa)
 dapoxetine (Priligy)
 escitalopram (Lexapro)
 fluoxetine (Prozac)
 fluvoxamine (Luvox)
 paroxetine (Paxil)
 sertraline (Zoloft)
 zimelidine (Zelmid) (discontinued)
 indalpine (Upstene) (discontinued)
Fluoxetine 1:1
Sertraline

 More trade names once patent is over but I kept
original trade names
 Citalopram: Major depression
 Dapoxetine: Premature Ejaculation
 Escitalopram: Major depression and various other
anxiety disorders
 Fluxoetine: Major depression, OCD, bulimia, etc
 Fluvoxamine: OCD
 Paroxetine: Major depression or anxiety
 Sertraline: Major depression or anxiety
 Zimelidine had neurological problems like
Guillan Barre
 Indalpine had problems with fetal low WBC

 Exact mechanism remains uncertain
 Ser-438 residue in the human serotonin
transporter (hSERT) appears to be a
determining factor in SSRI potency
 Antidepressants interact directly with hSERT
 http://www.mayoclinic.com/health/antidepre
ssants/MM00660

 Anhedonia
 Apathy
 Nausea/vomiting
 Drowsiness or
somnolence
 Headache
 Bruxism (involuntarily
grinding of the teeth)
 Extremely vivid and
strange dreams
 Dizziness
 Fatigue
 Changes in sexual
behavior
 Suicidal thoughts

 Many disappear within 4 weeks (adaption
phase)
 Side effects more manageable compared to
MAOIs and TCAs
 Sexual side effects are common
 SSRI cessation syndrome
 Brain zaps
 Sexual dysfunction

 Slightly greater efficacy than SSRIs
 Slightly fewer adverse effects than SSRIs
 Current drugs
 Venlafaxine (Effexor)
 Duloxetine (Cymbalta)
 Very similar to SSRIs
 Works on both neurotransmitters
 Side effects
 Similar to SSRIs
 Suicide
Venlafaxine 1:1
Duloxetine

 Current drugs
 Bupropion (Wellbutrin)
 Mechanims of Action
 Similar to SSRIs and SNRIs
 More potent in inhibiting dopamine
 Also anα3-β4 nicotinic antagonist
 Adverse effects
 Lowers seizure threshold
 Suicide
 Does not cause weight gain or sexual dysfunction
(even used to treat the two)
Bupropion 1:1

 The overactive point of view
 In some depressives CSF 5-HT is elevated
 Approx. 30% of depressed patients do not respond to
SSRIs
 Depletion of 5-HT by inhibition of tryptophan
hydroxylase (TH) alleviates depressive symptoms in
some patients
 Tianeptine, a 5-HT reuptake enhancer that works
opposite to SSRIs, is a marketed antidepressant
 A selective TH inhibitor shows activity in an animal
model of depression
 The activation of TH by stress can be blocked by
Prozac

 Indications: depression, panic and phobias, OCD,
enuresis, anorexia nervosa, bulimia
 Drug Choice: past response, tolerance to side
effects, drug-drug interactions
 Treatment: 1-6 months; recent report suggests
changing if no improvement by 4 weeks
 Note: All antidepressants now carry a “black
box” warning that they may lead to suicidal
thoughts/behavior

 increased energy
(buying, phoning, sex)
 increased
gregariousness
 pressured speech,
talkativeness
 decreased sleep
 drunkenness
 combative, dangerous
behavior
 distractibility
 racing thoughts
 impulsive actions and
decisions
 elevated mood
 euphoria
 grandiosity
 irritability/hostility
(easily angered)

MANIA—too much neurotransmission?
Increased production of inositol phosphate (IP-3) which
increases intracellular Ca2+ signalling
Increased DAG which:
activates PKC which phosphorylates a number of
substrates including myristoylated alanine rich C
kinase (MARCK)
MARCK activates nuclear transcription factors and
modulates genes that increase neuromodulatory
peptide hormones and alters cell signalling which:
changes neurotransmitter synthesis
neuronal excitabiltiy
synaptic plasticity
neuronal cell loss (prefrontal cortex?)

 a monovalent ion that can enter neurons
but is not readily removed.
 major mechanism is the reduction of
neuronal PI second messenger resulting in
reduced response of neurons to ACh and
NE
 may actually enhance 5-HT

 primary therapy for mania
 a narrow therapeutic window (0.8-1.2
meq/L; some guides say 0.6-1.4 meq/L)
 absolutely necessary to monitor serum
level (trough level approx. 5 days after
initial dose)
 solely eliminated by kidney, therefore
assess patient’s kidney function

 tremor
 decreased thyroid function
 polydipsia/polyuria
 edema
 ECG changes (depression of T-wave)
 excreted in breast milk

 Anticonvulsants: carbamazepine and
valproic acid for rapid cyclers
 Olanzepine approved for treatment of
mania
 St. John’s Wort: questionable efficacy,
but high potential for drug-drug
interactions

 Features of illness,
e.g. agitation,
hypersomia
 Suicide risk
 Other therapy
 Other illness.
 Side effects
 Cost
 Special problems
e.g. Age, driving,
pregnancy

 Non compliance.
 Inadequate dosage.
 Other drugs e.g. alcohol, caffeine.
 Unresolved outside problems.
 Up to 26% failure even if above don’t apply.

 Realm of specialists
 Lithium,
carbamazepine
 Mixtures i.e. SSRI
and TCA
 Dangerous – need
expert supervision

 NEUROENDOCRINE THEORY
 Depression is associated with elevated
plasma cortisol level that is due to
excessive release of hypothalamic CRH.

 This elevated CRH may reflect defective
monoamine transmission.
 N.B hypothalamic neurons controlling
pituitary function receive noradrenergic and
serotonergic inputs which control their
discharge

 This theory is supported by:
 High CRH concentration in brain & CSF in
depressed patients
 High plasma cortisol level in depressed
patients
 CRH injected into brain of experimental
animals gives symptoms like that of
depression
 Cushing’s syndrome is often associated with
depression


 NEURODEGENERATION THEORY
 Major depression may be associated with
neurodegeneration in the hippocampus &
prefrontal cortex and antidepressants may
act by inhibiting or actually reversing this
loss by stimulating neurogenesis

 This theory is supported by:
 Imaging studies showed shrinkage of hippocampus &
prefrontal cortex of depressed patients
 Functional imaging reveals reduced neural activity in these
regions
 Antidepressants promote neurogenesis in these regions and
restore functional activity
 Preventing hippocampal neurogenis in depressed rats
prevents the behavioral effects of antidepressants

Antidepressants increase the production of brain derived
neurotrophic factor (BDNF) which promotes neurogenesis
and protects neurons against apoptosis




Antidepressant drugs

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