MNR College of Pharmacy

Topic: Affective disorders

Professor: Dr. M.Vinyas

 Introduction
The term affective is related to feelings, mood
or emotion.
Hippocrates first coined the term
“melancholia” meaning “unshakable sadness”.
Today known as depression
So, affective disorder is a group of disorder
that are related to mood and mainly include
depression, mania and anxiety.
 What is affective disorder?
Mood is a person’s subjective emotional
state
Affect is the objective appearance of
mood
Mood disorders involve a depression or
elevation of mood as the primary
disturbance
Can have other abnormalities such as
anxiety.
 Characterization
Affective disorder is mainly
characterized by:
Depression
Anxiety
Mania
1. Major depression (Unipolar
Depression)

2. Manic depressive illness (Bipolar

Depression)
 1. Major Depressive Episode
Depressed mood Fatigue or low energy
Anhedonia Feelings of worthlessness
Decrease or increase in or inappropriate guilt
Decreased concentration
appetite OR significant
weight loss or gain or indecisiveness
Persistently increased or Recurrent thoughts of

decreased sleep death, suicidal ideation,

Psychomotor agitation
or suicide attempt
or retardation
Five or more symptoms present for ≥ 2 weeks
 2. Manic depressive illness
(Bipolar Depression)
Psychosis is a symptom of mental illnesses
characterized by a distorted or non-existent sense
of reality. Psychotic disorders have different
etiologies, each of which demands a unique
treatment approach. Common psychotic disorders
include major depression or mania with psychotic
features, substance-induced psychosis, dementia
with psychotic features, brief psychotic disorder,
delusional disorder, schizophrenia.
 Symptoms of Anxiety
Anxiety disorders encompass a constellation of
symptoms, and include generalized anxiety
disorder, obsessive-compulsive disorder, panic
disorder, post-traumatic stress disorder,
separation anxiety disorder, social phobia,
specific phobias, and acute stress.
 Symptoms of anxiety also are often associated
with depression and other medical conditions.
Anxiety is common in MDD and bipolar
disorder; however, may be a separate diagnosis.
Major Depressive Disorder
 Presence of a major depressive
episode

 Episode not better explained by

another diagnosis

 NO HISTORY of mania, hypomania,

or mixed episode.
 Major Depressive Disorder
Lifetime risk:
◦ 10%-25% for women
◦ 5%-12% for men
Family history of MDD increases risk 1.5-3
times
Up to 20%-25% of patients with major
medical comorbidity (CVD, diabetes,
cancer) will develop MDD
Average age of onset in mid-20’s
 Major Depressive Disorder:
Treatment basics
Medications:
◦ Selective serotonin reuptake inhibitors (SSRIs)
◦ Tricyclic antidepressants (TCAs)
◦ Monoamine oxidase inhibitors (MAOIs)
◦ Other: venlafaxine, mirtazapine, nefazodone,
bupropion
Psychotherapy:
◦ Cognitive-behavioral therapy (CBT)
◦ Interpersonal therapy (IPT)
◦ Psychodynamic psychotherapy (e.g., psychoanalysis)
Other
◦ Electroconvulsive therapy (ECT)
◦ Light therapy – primarily for SAD
 Major Depressive Disorder:
Medications
Treatment choice based on:
◦ Severity
◦ Side effect profile
◦ Risk of overdose
◦ Other diagnoses (e.g., anxiety)
◦ ?Family history of treatment response
If psychosis is present, this must be treated
Medications may take up to 6 (8? 12?) weeks
to be maximally effective
Efficacy 60%-80% overall (50%-60% for
each)
 Bipolar I Disorder
At least one manic or mixed episode
No need for a prior depressive
episode
General Comments
Symptoms cause significant
impairment in social and/or
occupational functioning.
Symptoms do not result from a
drug of abuse, medication, other
treatment, or general medical
condition
 Manic Episode
Elevated (or irritable) mood for >1 week
Three or more of following (four if mood irritable):

 Grandiosity  Distractibility
 Decreased need for  Increased goal-
sleep directed activity
 Flight of ideas,  Excessive
racing thoughts involvement in
pleasurable
activities with high
risk
 Causes
Norepinephrine and serotonin
cause functional deficit at specific
nerve cell synapses that is
associated with depression
On the other hand, excess of these
neurotransmitters leading to mania.
Biogenic Theory of Depression

 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.

Amine neurotransmitters are
either degraded (metab)
or reuptaken

MAO

Mito

COMT
The purpose of antidepressants is the
increase the [neurotransmitters] in
the synapse
Depression and Mania
Monoamine Theory of Mental Depression
Depression is linked to low levels of
norepinephrine and/or serotonin.
Mania is linked to high levels of
norepinephrine and/or serotonin.
Bipolar mood disorder is alternating cycles
of depression and mania.
 Drugs Used to Treat Depression
Drugs that increase the level of
norepinephrine and serotonin are used in
the treatment of depression.
Major antidepressant drug classes:
◦ Serotonin reuptake inhibitors (SSRIs)
◦ Atypical SSRIs
◦ Tricyclic antidepressants (TCAs)
◦ Monoamine oxidase inhibitors (MAOIs)

14-21
 TREATMENT FOR DEPRESSION

Psychotherapy
Electroconvulsive therapy
Natural alternatives
Medication
 SSRIs
 MAOIs
 TCAs
 SNRIs
 NDRIs
 TeCAs
 NEUROTRANSMITTERS AND
THE CATECHOLAMINE
HYPOTHESIS
Neurotransmitters pass along signal
Smaller amount of neurotransmitters causes
depression
 MONOAMINE OXIDASE (MAO) AND
DEPRESSION
MAO catalyze deamination of
intracellular monoamines
◦ MAO-A oxidizes epinephrine, norepinephrine,
serotonin
◦ MAO-B oxidizes phenylethylamine
◦ Both oxidize dopamine nonpreferentially
MAO transporters reuptake extracellular
monoamine
MONOAMINE OXIDASE INHIBITORS (MAOIS)

History
◦ Isoniazid
◦ Iproniazid
Isoniazid

Iproniazid
 MAOIs
New antidepressant introduced
but withdrawn due to liver
O O
H
N CH3
toxicity, however, increased
NH2
N N
H
interest on hydrazines and
H
N N CH3 hydrazides for antidepressants
Isoniazide Iproniazide
Antitubercular but too Antitubercular but CNS
polar stimulant
Which later shown to be hydrazines
MAOI resulting in NE & 5-
HT
 Thus MAOIs based on the hydrazine molecule have been extensively studied. Hydrazine,
itself, has no MAOI activity
 Must have a free amino at one end to be active; a protonatable terminal N is necessary;
those without a terminal N are prodrugs and must be bioactivated
 Must have at least one free hydrogen on each nitrogen
Monoamine Oxidase
Monoamine oxidase (MAO) is an
enzyme found in adrenergic and
serotonergic nerve endings.
Normal function of MAO is to break
down norepinephrine and serotonin.
In mental depression, there appears to
be a decrease in the levels of brain
norepinephrine and serotonin.
Monoamine Oxidase Inhibitors
Consequently, the MAO inhibitors permit
the levels of NE and serotonin in the brain
to increase.
They have many drug interactions;
caution must be exercised with use of
other drugs.
 Monoamine Oxidase Inhibitor
Disadvantages of MOAIs:
◦ Dietary restrictions—tyramine
 Wine, beer, herring, certain cheeses
Adverse effects:
◦ Dry mouth, urinary retention, constipation,
blurred vision, hypotension, weight gain, sexual
dysfunction, liver damage that may be fatal
◦ CNS: restlessness, dizziness, insomnia, tremors,
seizures, (intensified with over dosage)
 Monoamine Oxidase Inhibitor

14-30
 MAOIS ON THE MARKET

MAO Inhibitors (nonselective)

◦ Phenelzine (Nardil)
◦ Tranylcypromine (Parnate)
◦ Isocarboxazid (Marplan)
MAO-B Inhibitors (selective for MAO-B)
◦ Selegiline (Emsam)
 MAOIS MECHANISM OF ACTION

MAO contains
a cysteinyl-
linked flavin
MAOIs
covalently bind
to N-5 of the
flavin residue
of the enzyme
MAOIS SIDE EFFECTS
 Drowsiness/Fatigue  Muscle twitching
 Constipation  Weight gain
 Nausea  Blurred vision
 Diarrhea  Headache
 Dizziness  Increased appetite
 Low blood pressure  Restlessness
 Lightheadedness,  Shakiness
 Decreased urine output  Weakness
 Decreased sexual  Increased sweating
function
 Sleep disturbances
 MAOIS SIDE EFFECTS
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
 THE RECEPTOR SENSITIVITY
HYPOTHESIS
Supersensitivity and up-regulation of
post-synaptic receptors leads to
depression
Suicidal and depressed patients have
increased 5HT-α2 receptors
 Tricyclic Antidepressants
Drugs that block the reuptake of
norepinephrine and serotonin back
into the neuronal nerve endings
Produce varying degrees of sedation,
anticholinergic effects, and alpha-
adrenergic blocking effects

14-37
 Tricyclic Antidepressants

14-38
 Tricyclic Antidepressants
• TCAs with a tertiary-amine side chain, including amitriptyline,
doxepin, and imipramine, inhibit both norepinephrine and
serotonin uptake.
• Clomipramine is somewhat selective for inhibition of serotonin
uptake.
• Chemical modification of the TCA structure led to the earliest
SSRI zimelidine.
• Imipramine has a phenothiazine-like structure (unlike the
phenothiazines) had limited efficacy in schizophrenic patients,
but improved symptoms of depression.
• Imipramine and related TCAs became the mainstay of drug
treatment of depression until the later development of the SSRIs
 Tricyclic Antidepressants
• TCAs with a tertiary-amine side chain, including
amitriptyline, doxepin, and imipramine, inhibit both
norepinephrine and serotonin uptake.
• Clomipramine is somewhat selective for inhibition of
serotonin uptake. Chemical modification of the TCA
structure led to the earliest SSRI zimelidine which, while
effective, was withdrawn from the market due to serious
adverse effects.
•One of the compounds, imipramine, which has a
phenothiazine-like structure, modified behavior in animal
models. Unlike the phenothiazines, imipramine had
limited efficacy in schizophrenic patients, but improved
14-40
symptoms of depression. Imipramine and related TCAs
became the mainstay of drug treatment of depression until
the later development of the SSRIs
 TRICYCLIC ANTIDEPRESSANTS
(TCAS)
 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 Imipramine
severe depression, but it’s
almost too good – also causes
hypomania and mania
TCAS MECHANISM OF ACTION
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
TCAS MECHANISM OF ACTION
 TCAS SIDE EFFECTS
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)
 SELECTIVE SEROTONIN REUPTAKE
INHIBITORS
Most commonly prescribed class
Current drugs
Mechanism of action
Side effects

Serotonin
Selective Serotonin Reuptake Inhibitors
SSRIs were introduced from 1984-1997.
 including fluoxetine, paroxetine, sertraline, citalopram,
escitalopram, and fluvoxamine.
The FDA has approved fluvoxamine for treatment of
obsessive-compulsive disorder and social anxiety
disorder, but not depression.
Citalopram is labeled for use in premenstrual dysphoric
disorder.
All of the SSRIs show a clear improvement in safety
margin compared to the TCAs and are much safer in
overdose.
Selective Serotonin Reuptake Inhibitors
The SSRIs are effective in treating major
depression.
In typical studies SSRI treatment results in ~ 35%
of patients enjoying a remission,
SSRIs also are anxiolytics with demonstrated
efficacy in the treatment of generalized anxiety,
panic, social anxiety, and OCD.
Sertraline and paroxetine also have been approved
for the treatment of posttraumatic stress disorder
(PTSD).
Selective Serotonin Reuptake Inhibitors
SSRIs block the reuptake of serotonin back into
the serotonergic nerve endings.
This increases the serotonin available to work
on the system.
SSRIs are relatively selective, that is, 10-fold or
more, for inhibition of SERT relative to NET.
SSRIs are the preferred treatment for major
depression and effective for PTSD and OCD.
Selective Serotonin Reuptake Inhibitors

• SSRI treatment causes stimulation of 5-HT1A and 5-

HT7 autoreceptors on cell bodies in the raphe nucleus
and of 5-HT1D autoreceptors on serotonergic terminals.

• With repeated treatment with SSRIs, there is a

gradual down-regulation and desensitization of these
autoreceptor mechanisms.
• In addition, down-regulation of postsynaptic 5-HT2A
receptors may contribute to antidepressant efficacy
directly or by influencing the function of
noradrenergic and other neurons via serotonergic
heteroreceptors.
 SSRI: Pharmacokinetics
• All of the SSRIs are orally active and possess
elimination half-lives consistent with once-daily
dosing .
• In the case of fluoxetine, the combined action
of the parent and the desmethyl metabolite
norfluoxetine allows for a once weekly
formulation (PROZAC WEEKLY).
• CYP2D6 is involved in the metabolism of
most SSRIs and the SSRIs are at least
moderately potent inhibitors of this
isoenzyme. .
1-50
 Selective Serotonin Reuptake Inhibitors

• This creates a significant potential for drug interaction for

post-menopausal women taking the breast cancer drug and
estrogen antagonist, tamoxifen .
• The parent molecule is converted to a more active metabolite
by CYP2D6.
• SSRIs may inhibit this activation and diminish the therapeutic
activity of tamoxifen.
• Since venlafaxine and desvenlafaxine are weak inhibitors of
CYP2D6, these antidepressants are not contraindicated in this
clinical situation.
• However, care should be used in combining SSRIs with drugs
that are metabolized by CYPs 1A2, 2D6, 2C9, and 3A4 (e.g.,
warfarin, tricyclic antidepressants, paclitaxel).
Selective Serotonin Reuptake Inhibitors

Adverse effects:
◦ GI disturbances
◦ Dry mouth
◦ Sexual dysfunction
◦ Headache
◦ Nervousness
◦ Insomnia
◦ Tremors
Selective Serotonin Reuptake Inhibitors

The SSRIs, unlike the TCAs, do not

cause major cardiovascular side effects.
The SSRIs are generally free of
antimuscarinic side effects (dry mouth,
urinary retention, confusion),
Do not block histamine or adrenergic
receptors, and are not sedating.
Selective Serotonin Reuptake Inhibitors
Excessive stimulation of brain 5-HT2
receptors may result in insomnia,
increased anxiety, irritability, and
decreased libido, worsening prominent
depressive symptoms.
Excess activity at spinal 5-HT2 receptors
causes sexual side effects including
erectile dysfunction, and ejaculatory delay.
Selective Serotonin Reuptake Inhibitors

Stimulation of 5-HT3 receptors

in the CNS and periphery
contributes to GI effects- nausea,
diarrhea and emesis.
 Selective Serotonin Reuptake Inhibitors

14-56
 Atypical SSRIs
They block reuptake of serotonin and
act on other neurotransmitters and
receptors as well. (NE and/or
Dopamine)

Like the SSRIs, they have little effect

in blocking cholinergic, adrenergic, or
histamine receptors.
14-57
Atypical SSRIs
Atypical SSRIs:Bupropion
Appears to act via multiple mechanisms: enhances
noradrenergic and dopaminergic neurotransmission
via reuptake inhibition
Also involve the presynaptic release of NE and DA .
Indicated for depression, prevention of seasonal
depressive disorder, and as a smoking cessation
treatment .
Improve symptoms of attention deficit hyperactivity
disorder (ADHD).
Used in combination with SSRIs to obtain a greater
antidepressant response.
 Atypical SSRIs:Bupropion

The terminal phase of bupropion

elimination has a t1/2 of 21 hours.
The elimination involves both hepatic
and renal routes.
Decreased dose should also be made in
cases of renal impairment.
 Atypical SSRIs:Bupropion
Adverse effects:
At doses higher than that recommended
for depression (450 mg/day), the risk of
seizures increases significantly.
The use of extended release
formulations often blunts the maximum
concentration observed after dosing.
 Atypical SSRIs:Bupropion
Drug interaction:
The major route of metabolism is
CYP2B6.
Does not appear to be metabolised by
CYP2D6 and this drug is frequently
administered with SSRIs.
 Drug interaction : Selective
Serotonin Reuptake Inhibitors
Paroxetine, fluoxetine are potent
inhibitors of CYP2D6.
This inhibition can result in
disproportionate increases in plasma
concentrations of drugs metabolized by
CYP2D6.
 A prominent interaction is the increase in
TCA exposure that may be observed
during co-administration of TCAs and
SSRIs.
 Drug interaction : Selective
Serotonin Reuptake Inhibitors
MAOIs enhance the effects of SSRIs due to
inhibition of serotonin metabolism.
Administration of these drugs together can
produce synergistic increases in extracellular brain
serotonin, leading to the serotonin syndrome.
Other drugs that may induce the serotonin
syndrome include:
methylenedioxymethamphetamine.
 Drug interaction : Selective
Serotonin Reuptake Inhibitors
SSRIs should not be started until at
least 14 days following discontinuation
of treatment with an MAOI.
For all SSRIs, 14 days should pass prior
to beginning treatment with an MAOI
following the end of treatment with an
SSRI. Exception: fluoxetine.
 Atypical SSRIs:Bupropion
Drug interaction:
The major route of metabolism is
CYP2B6.
Does not appear to be metabolised by
CYP2D6 and this drug is frequently
administered with SSRIs.
 Atypical SSRIs:Bupropion
Drug interaction:
The major route of metabolism is
CYP2B6.
Does not appear to be metabolised by
CYP2D6 and this drug is frequently
administered with SSRIs.
 Atypical SSRIs:Bupropion
Drug interaction:
The major route of metabolism is
CYP2B6.
Does not appear to be metabolised by
CYP2D6 and this drug is frequently
administered with SSRIs.
SSRIS SIDE EFFECTS
Anhedonia Extremely vivid
Apathy and strange dreams
Nausea/vomiting Dizziness
Drowsiness or Fatigue
somnolence Changes in sexual
Headache behavior
Bruxism Suicidal thoughts
(involuntarily
grinding of the
teeth)
 Summary
Q: What was the first Antidepressant, and what
is its mech of action?
Iproniazid

Q: Describe the clinical effects of tyramine

toxicity
ncreases the release of NE
When a person is on an MAOI and also
consumes tyramine containing foods/drinks,
there is NE overload which can cause
hypertensive crisis.
 MAOIs

Second line treatment, due to side

effect profile
potentially lethal food and drug
interactions
Still used for refractory depression
Adverse Effects of TCA's 
Significant Overdose Potential due to narrow
therapeutic window.
 Cardiovascular Toxicity (potential for fatal cardiac
arrythmia).
Side effects:
anti-histaminergic (weight gain, drowsiness)
anti-cholinergic (constipation, blurred vision, dry
mouth, drowsiness again)
anti-alpha adrenergic (dizziness, decreased BP)

)
Compare the efficacy and side effects for
Secondary amine TCA's vs Tertiary amine TCA's
Tertiary amines have greater alpha,
histamine 1, and muscarinic blockade.
Secondary amines are newer, have fewer
side effects, are less sedating, and hold less
overdose risk.
 Issues in antidepressant therapy

Important issue in the use of antidepressants is

a phenomenon known as the "switch" from a
depressed episode to a manic or hypomanic
episode, a challenge in managing bipolar
illness.
For this reason, antidepressants are not
recommended as monotherapy for bipolar
illness.
SSRIs and bupropion may be somewhat less
likely to induce the switch from depression to
mania than antidepressants from other
pharmacological classes.
 Issues in antidepressant therapy

A controversial issue regarding the use of

all antidepressants is their relationship to
suicide.
The FDA has issued a "black box"
warning regarding the use of SSRIs and a
number of other antidepressants in
children and adolescents, particularly
during the early phase of treatment, due to
the possibility of an association between
antidepressant treatment and suicide.
Drugs

Serotonin Receptor Antagonists

Several antagonists of the 5-HT2 family of
receptors are effective antidepressants,
although most agents of this class affect other
receptor classes as well. The class includes two
pairs of close structural analogues, trazodone
and nefazodone, as well as mirtazapine and
mianserin (not marketed in the U.S.).
the nucleus of the brain that uses serotonin, and
locations to which its neurons project:

5HT neurons project to:

Frontal
Limbic
Brainstem
Hypothalamus
Serotonin Antagonist & Reuptake
Inhibitors
Its an SSRI that also blocks the 5HT2A-R
(overall, its less activating and more
sedating than the SSRI's
Used to treat depression, anxiety, insomnia
AND no associated weight gain OR sexual
dysfunction
Adverse:  Sedation, orthostatic
hypotention, priapism (rare
Yet its rarely used, not 1st line
 Serotonin vs Norepinephrine
 Therapeutic Effects and Side Effects
Overall,Serotonin is more of a calming agent, NE
more of a stimulating agent
Serotonin - therapeutically acts on mood, anxiety,
and obsessions
NE - acts on mood, attention, and improves low
energy states.
Serotonin side effects - sexual dysfunction, GI,
Insomnia, Akasthesia
NE side effects - Tremor, elevated BP/HR, urinary
retention
 5-HT1 Receptors

preferentiallycouple to Gi/o ; inhibit adenylyl cyclase.

 The 5-HT1A, 5-HT1B, & 5-HT1D activate a receptor-
operated K+ channel and inhibit a voltage-gated Ca2+
channel.
The 5-HT1A is found in raphe nuclei of the brainstem-
functions as an inhibitory, somatodendritic
autoreceptor on cell bodies of serotonergic neurons.
Another 5-HT1 subtype, the 5-HT1D/1B, functions as
an autoreceptor on axon terminals, inhibiting 5-HT
release.
 5-HT2 Receptors

3subtypes of 5-HT2 couple to Gq/G11 proteins and

activate phospholipase C, generating 2 second
messengers: diacylglycerol and inositol trisphosphate.
5-HT2A and 5-HT2C receptors also activate
phospholipase A2 -release of arachidonic acid.
5-HT2A : broadly distributed in the CNS, serotonergic
terminal. Also in prefrontal, parietal, and
somatosensory cortex, in blood platelets and smooth
muscle cells.
5-HT2B found in stomach fundus, where they are
abundant. The expression of 5-HT2B receptors is
highly restricted in the CNS.
 5-HT3 Receptors

The 5-HT3 receptor is the only monoamine

neurotransmitter receptor function as a ligand-
operated ion channel.
 Activation of 5-HT3 elicits a rapidly desensitizing
depolarization, mediated by the gating of cations.
Located on parasympathetic terminals in the GI tract,
including vagal and splanchnic afferents. In the CNS,
in the solitary tract nucleus and in the area postrema.
5-HT3 receptors in both the GI tract and the CNS
participate in the emetic response, providing a basis
for the anti-emetic property of 5-HT3 receptor
antagonists.
 5-HT4 Receptors

5-HT4 couple to Gs to activate adenylyl cyclase.

distributed throughout the body. on neurons of the
superior and inferior colliculi and in the hippocampus
in CNS.
In the GI tract, 5-HT4 are located on neurons of the
myenteric plexus and on smooth muscle and secretory
cells.
Stimulation of the 5-HT4 receptor evokes secretion and
facilitates the peristaltic reflex.
 Effects of pharmacological manipulation of 5-HT4
receptors on memory and feeding in animal models
suggest possible clinical applications in the future
 5-HT Receptors on CNS

A multitude of brain functions are influenced by 5-HT,

including sleep, cognition, sensory perception, motor
activity, temperature regulation, nociception, mood,
appetite, sexual behavior, and hormone secretion.
The principal cell bodies of 5-HT neurons are located
in raphe nuclei of the brainstem and project
throughout the brain and spinal cord.
release of serotonin occurs at sites of axonal swelling,
termed varicosities, which do not form distinct
synaptic contacts. Such non-synaptic release is
consistent with the idea that 5-HT acts as a
neuromodulator as well as a neurotransmitter.
 Sleep-Wake Cycle

Control of the sleep-wake cycle is one of the

first behaviors in which a role for 5-HT was
identified.
Depletion of 5-HT with p-
chlorophenylalanine, a tryptophan
hydroxylase inhibitor, elicits insomnia that is
reversed by the 5-HT precursor, 5-
hydroxytryptophan.
Conversely, treatment with L-tryptophan or
with nonselective 5-HT agonists accelerates
sleep onset and prolongs total sleep time.
 Aggression and Impulsivity

5-HT serves a critical role in aggression and

impulsivity.
Pharmacological studies of aggressive
behavior in laboratory animals suggest a role
for 5-HT.
5-HT1B receptors in the development of
neuronal pathways important in aggression or
a direct role in the mediation of aggressive
behavior.
Anxiety and Depression
The effects of 5-HT–active drugs in anxiety
and depressive disorders, like the effects of
selective serotonin reuptake inhibitors
(SSRIs), strongly suggest a role for 5-HT in
the neurochemical mediation of these
disorders. Mutant mice lacking the 5-HT
transporter display anxiety and a
"depressive-like" phenotype.
Anxiety and Depression
 Mech of Action: Serotonin-
Norepinephrine Reuptake Inhibitors
SNRIs inhibit both SERT and NET. SNRIs cause
enhanced serotonergic and/or noradrenergic
neurotransmission.
Similar to the action of SSRIs, the initial
inhibition of SERT induces activation of 5-HT 1A
and 5-HT1D autoreceptors.
This action decreases serotonergic
neurotransmission by a negative feedback
mechanism until these serotonergic autoreceptors
are desensitized.
Then, the enhanced serotonin concentration in the
synapse interact with postsynaptic 5-HT receptors.
 Serotonin Receptor Antagonists
antagonists of the 5-HT2 are effective
antidepressants, although most agents of this
class affect other receptor classes as well.
The class includes two pairs of close structural
analogues, trazodone and nefazodone,
mirtazapine (REMERON, others) and mianserin.
Trazodone and nefazodone block 5-HT2 and alfa1
adrenergic receptors. Trazodone also inhibits the
serotonin transporter, but is markedly less potent
relative to its blockade of 5-HT2A receptors.
Differential Diagnosis:
Other mood and anxiety disorders
Symptoms of mood disorders may
overlap (e.g., dysthymia and MDD)
Diagnosis is often based on history – and
patient’s memory of past symptoms may
be unreliable
 Medical conditions
Thyroid abnormalities Stroke
Cortisol abnormalities Huntington’s disease
Parkinson’s disease Chronic infections
Multiple sclerosis Certain medications:
Epilepsy ◦ Steroids
Brain tumor ◦ Interferon
Cancer (e.g., ◦ Beta-blockers
pancreatic) ◦ Isotretinoin (Accutane)
Dementia ◦ Oral contraceptives
Traumatic brain injury ◦ Antidepressants (!!)
Autoimmune disorders ◦ Everything else?!?
Substance-induced mood disorder
Alcohol: depression PCP, ketamine:
Cocaine: hypomania, hypomania, mania
mania Heroin: depression?
Amphetamines:
Marijuana:
hypomania, mania
depression?
 Mood symptoms with intoxication or
withdrawal
 May take weeks-months to normalize mood
 Substance use highly comorbid in mood
disorders
(bipolar I > bipolar II > MDD)
Long-term effects: Antidepressant drugs
Long-term effects of antidepressant drugs evoke
adaptive or regulatory mechanisms that enhance
the effectiveness of therapy. These responses
include increased adrenergic or serotonergic
receptor density or sensitivity, increased
receptor-G protein coupling and cyclic
nucleotide signaling, induction of neurotrophic
factors, and increased neurogenesis in the
hippocampus. hanced serotonergic or
noradrenergic neurotransmission achieved by an
alternative pharmacological mechanism.
Long-term effects: Antidepressant drugs
Chronic treatment with some antidepressants
that interact directly with monoamine
transporters (e.g., SSRIs, SNRIs, or NE reuptake
inhibitors) reduces the expression and activity of
5-HT or NE transporters in the brain, which
results in enhanced serotonergic or
noradrenergic neurotransmission. Sustained
signaling via NE or 5-HT increases the
expression of specific downstream gene
products, particularly brain-derived neurotrophic
factor (BDNF).
 Suggested history/workup
Review of current and Review of systems
past psych sx/dx Workup
◦ Get collateral history ◦ CBC
Review prior ◦ Electrolytes
treatments and ◦ Renal function
response ◦ Liver Function
Family history
◦ TSH
Medical history ◦ RPR?
Current medications ◦ HIV?
Substance use history ◦ Imaging?
Social history
 Treatment/management
ALWAYS ASSESS FOR SUICIDE!!!
◦ Ideation, plan, intent, means, risk factors
Choose medications carefully and
thoughtfully
Don’t give up too soon
Can always incorporate some behavioral and
CBT techniques (e.g., behavioral activation)
Address perpetuating factors (medical
problems, psychosocial stressors)
Treat the acute AND chronic aspects of the
illness (i.e., preventive management)
 Case #1a
Mr. M is a 34 y/o man who presents with 1-
month history of sad mood and decreased
motivation to go to work. He reports difficulty
falling asleep at night and multiple mid-cycle
awakenings. His appetite and energy are
normal.

◦ What other questions do you have?

◦ What is your working diagnosis?
◦ What is your initial treatment plan?
Case #1b
Mr. M returns one month later. He
continues to have sad mood, decreased
motivation, and feels that things are
getting worse.

◦ What other questions do you have?

◦ What is your working diagnosis?
◦ What is your treatment plan?
 Case #2a
Ms. T is a 19 y/o female college student who
presents to the emergency room with a several day
history of bizarre behavior at school. Her friends
say she hasn’t slept for 4-5 days, is talking “a mile
a minute,” and is trying to help everybody do their
homework stating, “you’ll never find a better tutor
than me!!”

◦ What other questions do you have?

◦ What is your working diagnosis?
◦ What is your treatment plan?
 Case #2b
Ms. T does well during the hospitalization
and is discharged in about 8 days. She
returns to clinic in 4 weeks and says she
thinks she’s ready to come off the
medication.

◦ What other questions do you have?

◦ What do you tell her?
 Case #2c
Ms. T stops her medications. She returns to
see you in another 4 weeks and tells you she
feels great – especially since she’s “off of
those mind-dulling drugs.” She feels much
more alert and is able to accomplish “more
than ever before.” She says she is doing well
with just 5 hours sleep per night and feels that
she’s finally “found” herself.
◦ What other questions do you have?
◦ What is your working diagnosis (has it changed)?
◦ What is your treatment plan?
 Case #2d
Ms. T refuses to re-start medications. Eight
weeks later, she is brought into the emergency
room after an acetaminophen OD. You
evaluate her during the medical
hospitalization. She reports 4-5 weeks of
worsening “emptiness,” difficulty falling
asleep, racing thoughts, and feeling “revved
up.” She has had increasing SI over the past
week.
◦ What other questions do you have?
◦ What is your working diagnosis (has it changed)?
Case #3a
Patientis a 6-7 y/o gray male donkey who
complains that “no one really cares about
me.” He states that he generally feels
down and never has enough energy.
◦ What other questions do you have?
◦ What is your working diagnosis?
◦ What is your treatment plan?
Case #3b
He returns 4 weeks later and tells you he
doesn’t really feel any better.
◦ What other questions do you have?
◦ What is your working diagnosis?
◦ What is your treatment plan?