Transcript What is affective disorder?

Affective Disorders
Overview
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What is a affective disorder?
Criteria for specific mood episodes and
disorders
Pharmacological intervention
Introduction
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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.
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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
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Depressed mood
Anhedonia
Decrease or increase in
appetite OR significant
weight loss or gain
Persistently increased or
decreased sleep
Psychomotor agitation or
retardation
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Fatigue or low energy
Feelings of worthlessness
or inappropriate guilt
Decreased concentration
or indecisiveness
Recurrent thoughts of
death, suicidal ideation,
or suicide attempt
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
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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
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Presence of a major depressive episode
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Episode not better explained by another
diagnosis
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NO HISTORY of mania, hypomania, or
mixed episode.
Major Depressive Disorder
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Lifetime risk:
10%-25% for women
 5%-12% for men
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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
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Major Depressive Disorder:
Treatment basics
Medications:
Selective serotonin reuptake inhibitors (SSRIs)
 Tricyclic antidepressants (TCAs)
 Monoamine oxidase inhibitors (MAOIs)
 Other: venlafaxine, mirtazapine, nefazodone,
bupropion
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Psychotherapy:
Cognitive-behavioral therapy (CBT)
 Interpersonal therapy (IPT)
 Psychodynamic psychotherapy (e.g., psychoanalysis)
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Other
Electroconvulsive therapy (ECT)
 Light therapy – primarily for SAD
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Major Depressive Disorder:
Medications
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Treatment choice based on:
Severity
 Side effect profile
 Risk of overdose
 Other diagnoses (e.g., anxiety)
 ?Family history of treatment response
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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
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Elevated (or irritable) mood for >1 week
Three or more of following (four if mood irritable):
Grandiosity
 Decreased need for sleep
 Flight of ideas, racing
thoughts
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Distractibility
 Increased goal-directed
activity
 Excessive involvement
in pleasurable activities
with high risk
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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
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Monoamine Theory of Mental Depression
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Depression is linked to low levels of
norepinephrine and/or serotonin.
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Mania is linked to high levels of norepinephrine
and/or serotonin.
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Bipolar mood disorder is alternating cycles of
depression and mania.
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Drugs Used to Treat Depression
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Drugs that increase the level of norepinephrine
and serotonin are used in the treatment of
depression.
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Major antidepressant drug classes:
Serotonin reuptake inhibitors (SSRIs)
 Atypical SSRIs
 Tricyclic antidepressants (TCAs)
 Monoamine oxidase inhibitors (MAOIs)
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TREATMENT FOR DEPRESSION
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Psychotherapy
Electroconvulsive therapy
Natural alternatives
Medication
SSRIs
 MAOIs
 TCAs
 SNRIs
 NDRIs
 TeCAs
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NEUROTRANSMITTERS AND THE
CATECHOLAMINE HYPOTHESIS
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Neurotransmitters pass along signal
Smaller amount of neurotransmitters causes depression
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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
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MAO transporters reuptake extracellular
monoamine
MONOAMINE OXIDASE INHIBITORS (MAOIS)
 History
 Isoniazid
 Iproniazid
Isoniazid
Iproniazid
MAOIs
O
O
N
N
H
NH2
Isoniazide
Antitubercular but too polar
N
N
H
H
N
CH3
CH3
Iproniazide
Antitubercular but CNS stimulant
Which later shown to be MAOI
resulting in 
NE & 5-HT
New antidepressant introduced but
withdrawn due to liver toxicity,
however,
increased
interest
on
hydrazines
and
hydrazides
for
antidepressants
H2N
NH2
hydrazines
 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
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Monoamine oxidase (MAO) is an enzyme
found in adrenergic and serotonergic nerve
endings.
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Normal function of MAO is to break
down norepinephrine and serotonin.
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In mental depression, there appears to be a
decrease in the levels of brain
norepinephrine and serotonin.
Monoamine Oxidase Inhibitors
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Consequently, the MAO inhibitors permit the
levels of NE and serotonin in the brain to
increase.
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They have many drug interactions; caution must
be exercised with use of other drugs.
Monoamine Oxidase Inhibitor
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Disadvantages of MOAIs:
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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)
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Monoamine Oxidase Inhibitor
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MAOIS ON THE MARKET
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MAO Inhibitors (nonselective)
Phenelzine (Nardil)
 Tranylcypromine (Parnate)
 Isocarboxazid (Marplan)
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MAO-B Inhibitors (selective for MAO-B)
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Selegiline (Emsam)
MAOIS MECHANISM OF
ACTION
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MAO contains
a cysteinyllinked flavin
MAOIs
covalently bind
to N-5 of the
flavin residue of
the enzyme
MAOIS SIDE EFFECTS
Drowsiness/Fatigue
 Constipation
 Nausea
 Diarrhea
 Dizziness
 Low blood pressure
 Lightheadedness,
 Decreased urine
output
 Decreased sexual
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Sleep disturbances
 Muscle twitching
 Weight gain
 Blurred vision
 Headache
 Increased appetite
 Restlessness
 Shakiness
 Weakness
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MAOIS SIDE EFFECTS
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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
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MAOIs interact with certain drugs
Serotonin syndrome (muscle rigidity, fever, seizures)
 Pain medications and SSRIs must be avoided
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THE RECEPTOR
SENSITIVITY HYPOTHESIS
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Supersensitivity and up-regulation of postsynaptic 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 alphaadrenergic blocking effects
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Tricyclic Antidepressants
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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
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• 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 symptoms of depression.
Imipramine and related TCAs became the mainstay of drug treatment of
depression until the later development of the SSRIs
•Fluoxetine and fluvoxamine were the first widely used SSRIs. At the same time,
selective inhibitors of norepinephrine reuptake entered clinical development;
while not approved for use in the U.S. for the treatment of depression, one
norepinephrine reuptake inhibitor, atomoxetine, is used for the treatment of
attention deficit hyperactivity disorder. Subsequent drug development efforts
focused on serotonin and norepinephrine reuptake inhibitors (SNRIs), resulting
in venlafaxine and duloxetine, which lack the complex receptor pharmacology
TRICYCLIC
ANTIDEPRESSANTS (TCAS)
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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
Imipramine
TCAS MECHANISM OF ACTION
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TCAs inhibit serotonin,
norepinephrine, and
dopamine transporters,
slowing reuptake
TCAs also allow for the
downregulation of postsynaptic receptors
All TCAs and SSRIs contain
an essential amino group that
appears to interact with Asp98 in hSERT
TCAS MECHANISM OF ACTION
TCAS SIDE EFFECTS
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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
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Most commonly prescribed class
Current drugs
Mechanism of action
Side effects
Serotonin
Selective Serotonin Reuptake Inhibitors
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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
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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
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SSRIs block the reuptake of serotonin back into
the serotonergic nerve endings.
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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.
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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 5HT7 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 5HT2A 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. .
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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).
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Selective Serotonin Reuptake
Inhibitors
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Adverse effects:
GI disturbances
 Dry mouth
 Sexual dysfunction
 Headache
 Nervousness
 Insomnia
 Tremors
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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
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Atypical SSRIs
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They block reuptake of serotonin and act
on other neurotransmitters and receptors
as well. (NE and/or Dopamine)
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Like the SSRIs, they have little effect in
blocking cholinergic, adrenergic, or
histamine receptors.
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Atypical SSRIs
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Atypical SSRIs:Bupropion
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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
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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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SSRIS SIDE EFFECTS
Anhedonia
 Apathy
 Nausea/vomiting
 Drowsiness or
somnolence
 Headache
 Bruxism (involuntarily
grinding of the teeth)
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Extremely vivid and
strange dreams
 Dizziness
 Fatigue
 Changes in sexual
behavior
 Suicidal thoughts
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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
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Second line treatment, due to side effect
profile
potentially lethal food and drug
interactions
Still used for refractory depression
Adverse Effects of TCA's
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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
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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.
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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.
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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.).
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the nucleus of the brain that uses
serotonin, and locations to which its
neurons project:
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5HT neurons project to:
Frontal
Limbic
Brainstem
Hypothalamus
Serotonin Antagonist & Reuptake
Inhibitors
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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
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Overall, Serotonin is more of a calming agent,
NE more of a stimulating agent
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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
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5-HT1 Receptors
preferentially couple to Gi/o ; inhibit adenylyl cyclase.
 The 5-HT1A, 5-HT1B, & 5-HT1D activate a receptoroperated K+ channel and inhibit a voltage-gated Ca2+
channel.
 The 5-HT1A is found in raphe nuclei of the brainstemfunctions 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.
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5-HT2 Receptors
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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
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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
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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
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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
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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, 5hydroxytryptophan.
Conversely, treatment with L-tryptophan or with
nonselective 5-HT agonists accelerates sleep onset
and prolongs total sleep time.
Aggression and Impulsivity
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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
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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
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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-HT1A 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
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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
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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
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Thyroid abnormalities
Cortisol abnormalities
Parkinson’s disease
Multiple sclerosis
Epilepsy
Brain tumor
Cancer (e.g., pancreatic)
Dementia
Traumatic brain injury
Autoimmune disorders
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Stroke
Huntington’s disease
Chronic infections
Certain medications:
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Steroids
Interferon
Beta-blockers
Isotretinoin (Accutane)
Oral contraceptives
Antidepressants (!!)
Everything else?!?
Substance-induced mood disorder
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Alcohol: depression
Cocaine: hypomania,
mania
Amphetamines:
hypomania, mania
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PCP, ketamine:
hypomania, mania
Heroin: depression?
Marijuana: 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)
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Long-term effects: Antidepressant
drugs
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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
Long-term effects: Antidepressant
drugs
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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
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Review of current and
past psych sx/dx
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Get collateral history
Review prior treatments
and response
Family history
Medical history
Current medications
Substance use history
Social history
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Review of systems
Workup
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CBC
Electrolytes
Renal function
Liver Function
TSH
RPR?
HIV?
Imaging?
Treatment/management
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ALWAYS ASSESS FOR SUICIDE!!!
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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
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Mr. M is a 34 y/o man who presents with 1month 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?
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Case #1b
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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?
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Case #2a
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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!!”
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What other questions do you have?
What is your working diagnosis?
What is your treatment plan?
Case #2b
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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?
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Case #2c
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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 minddulling 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?
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Case #2d
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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)?
 What is your treatment plan?
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Case #3a
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Patient is 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?
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Case #3b
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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?
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