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may contain information, ideas, concepts and
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insight, reflection or critical evaluation
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Psychopharmacology therapeutics The role of
Serotonin Dr. Craig Jackson Senior Lecturer
in Health Psychology Faculty of Health BCU
craig.jackson_at_bcu.ac.uk
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Depressive Illness Usually treatable Common Mark
ed disability Reduced survival Increased
costs Depression may be Coincidental
association Complication of physical
illness Cause of / exacerbate somatic symptoms
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Depressive Illness 2 of population suffer from
pure depression (evenly distributed between mild,
moderate, and severe) Further 8 suffer from a
mixture of anxiety and depression Patients with
symptoms not severe enough to qualify for
diagnosis of either anxiety or depression..... Im
paired working and social lives and many
unexplained physical symptoms Greater use of
medical services Walking Well
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• Classification
• Spectrum of mood disturbance
• Mild thru to Severe
• Transience thru to Persistence
• Continuous distribution in population
• Clinically significant when
• (1) interferes with normal activities
• (2) persists for min. 2 weeks
• Diagnosis of depression / depressive disorder
• Persistent pervasive low mood
• Loss of interest or pleasure in activities

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Classification Most depressions have triggering
life events - Reactive depression Especially in a
first episode Many patients present initially
with physical symptoms (somatisation) Some may
show multiple symptoms of depression in the
apparent absence of low mood - Masked
Depression Some depression has no triggering
cause - Endogenous Depression More persistent
and resistant to treatment
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• Clinical Features Diagnoses
• Adjustment Disorders
• mild
• short-lived
• reactive episodes
• Major Depressive Disorder (MDD)
• 5 symptoms displayed in 14 days
• Dysthmia
• depressed mood for 2 years
• not severe
• chronic depression
• unhealthy lifestyle associations
• Bipolar Disorder / manic depression
• major depression mania

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• Classification of Depression (ICD-10)
• PrimaryUnipolar
• Mixed anxiety and depressive disorder (prominent
  anxiety)
• Depressive episode (single episode)
• Recurrent depressive disorder (recurrent
  episodes)
• Dysthymia - Persistent and mild ("depressive
  personality")
• Bipolar
• Bipolar affective disorder - manic episodes
  ("manic depression")
• Cyclothymia - Persistent instability of mood
• Other primary
• Seasonal affective disorder
• Brief recurrent depression
• Depressive episode may be
• Moderate or severe
• With/Without somatic syndrome
• With/Without psychotic symptoms

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• DSM IV criteria Major depression
• 5 or more..
• decreased interest / pleasure
• depressed mood
• reduced energy
• weight gain / loss
• insomnia / hypersomnia
• feeling worthless
• guilt
• recurrent morbid thought
• psychomotor changes
• fatigue
• poor concentration
• pessimism / bleak views
• self harm ideas / actions
• suicide ideation

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• DSM IV criteria Major depression
• 4 or more...
• Anhedonia
• Loss of emotional reactivity
• Early waking (2 hours early)
• Psychomotor retardation or agitation
• Marked loss of appetite
• Weight loss 5 of body mass in one month
• Loss of libido

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• Classification
• Many patients do not fit neatly into categories
  of either anxiety or depression
• Mixed anxiety and depression is now recognised
• Presence of physical symptoms indicates a
  somatic syndrome
• Value of somatic features in predicting response
  to treatment is not clear
• Presence of psychotic features has major
  implications for treatment
• Brief episodes of more severe depression are
  also recognised
• (brief recurrent depression)
• More prolonged recurrence is now termed
  recurrent depressive disorder

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• Epidemiology
• 2nd biggest cause of disability
• worldwide by 2020 (WHO)
• (IHD still the biggest)
• Associated with increased
• physical illness
• 5 during lifetime have MDD
• 1 in 20 consultations
• 100 patients per GP
• MDD Dysthmia in females
• 20 develop chronic depression
• 30 of in-patients have depressive symptoms

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Epidemiology Depression more common in those
with Life threatened / limited / chronic
physical illness Unpleasant / demanding
treatment Low social support Adverse social
circumstances Personal / family history of
depression / psychological vulnerability Substan
ce misuse Anti-hypertensive / Corticosteroid /
Chemotherapy use
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Drug Treatment Tricyclics since the 1950s
effective and cheap dose-related
anticholinergic side effects limit compliance
variable degrees of sedation postural
hypotension may fatal in overdose (except
Lofepramine) Monoamine Oxidise Inhibitors
(MAOIs) rare fatalities tyramine-free
diet Selective Serotonin Re-uptake Inhibitors
(SSRIs) fluoxetine lack sedation no
anticholinergic effects improved compliance less
immediate benefit for disturbed sleep safe in
overdose single or narrow range of doses works
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Psychiatric Diagnoses in Juvenile Offenders 93
Conduct Disorder 82 Substance Abuse
Disorder 18 ADHD 26 Learning
Disabilities 32 Anxiety Disorders 22 Mood
Disorders 15 Associative Disorders Stanford
University, Division of Child Psychiatry
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Biology and Treatment of Aggression History and
Relationship with Suicidal Behaviour The Role
of Serotonin The Role of Other
Neurotransmitters Hormones Testosterone Ch
olesterol Opiates
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Serotonin 5-Hydroxytriptamine 5-HT 5-HT is a
neurotransmitter synthesised from amino acid
Tryptophan Metabolised to 5-Hydroxyindole Acetic
Acid (5-HIAA) Excreted in urine 3 - 15
mg/24hrs Elevated levels associated with
tumors Normal Range of 101 - 283 ng/ml
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The Association of Serotonin and Aggression Low
5-HT levels in suicide brains CSF 5-HIAA low
after suicide Animal studies - inverse
relationship between 5-HT and aggression e.g.
Higley et al. 1992 - rhesus monkeys PD patients
- inverse relationship between CSF 5-HIAA and
history of aggression e.g. Brown et al.
1985 5-HT at heart of psychopharmacology for
past 10 - 15 years
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CSF 5-HIAA and Aggression in Patients
Non-suicidal History n15 Suicidal History n9
5-HIAA ng/ml 00 20 40 60
0 4 8 12 16
20 24 Total
Aggression Score
Brown et al. 1979
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Psychopathology of Disruptive Behaviour
Disorders Stanford University,
Division of Child Psychiatry
Trauma Related Disorders
Personality Disorders
DISRUPTIVE BEHAVIOURDISORDERS
Mood Affective Disorders
Substances
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Violent Offender Studies Low 5-HIAA Impulsive
Aggression History of Suicide
Attempts Linoila et al. 1983
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Suicide Studies Low 5-HT Transporters Low
5-HT2A Receptors Stanley et al. 1982
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Pharmacotherapy for Impulsive Aggression Increase
inhibitors Increase 5-HT Reduce
Facilitators Reduce Catecholamines (adrenaline,
noradrenaline, dopamine) SSRIs can reduce CSF
Vassopressin Levels (peptide hormone) SSRIs can
reduce overt aggression (Coccaro Kavoussi 1997)

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Ecstacy and MDMA Ecstacy stimulates
serotoninProduces cells which turn on the
areas of the prefrontal cortexGive feelings of
euphoria, meaning and affectionsRegular users
in danger of burning out the cellsCreating risk
of temporary withdrawal symptoms and long-term
risk of chronic depression.
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Serotonin and MDMA use 40 minute cognitive
task Frascella et al. 1999
Control Chronic MDMA user
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Serotonin Hypothesis Pre-Synaptic 5-HT output
reduced Post-Synaptic receptor sensitivity
increased
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Serotonin Pathway
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Serotonin Neurotransmission
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Fenfluramine Centrally active
drug Benzeneethanamine, N-ethyl-alpha-methyl-3
(trifluoromethyl) Releases 5-HT Blocks 5-HT
uptake Provokes transport-mediated 5-HT
release Leads to Prolactin response Treatment
of obesity several psychiatric disorders
involving serotonergic systems
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Phentermine Central Nervous System
Stimulant Similar to Dextroamphetamine Benzene
ethanamine, alpha, alpha-dimethyl
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Fen-Phen Fenfluramine Phentermine Combination
therapy Wyaeth-Ayerst (Fen) 190 M in
1996 FDA powerless to stop it Some patients
report anxiety, impulsion, aggression
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Mood disorders are an illness - Treat them
! Drugs extremely effective Concentration,
mood, and thought control restored Mood
stabilizing drugs Role of Caffeine Tranquillizer
s Antipsychotics acute episodic use only E.C.T
effectiveness
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Too much Serotonin? Increased 5-HT in CNS and
receptor sites is therapeutic Benefits
in... Depression Panic Disorder OCD Bulimia
Toxic levels of 5-HT fever, myoclonus, coma,
seizure, cardiovascular collapse and
death Fen-Phen related to cardiac damage - drug
withdrawn
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Too much Serotonin?
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Selective Serotnin Re-uptake Inhibitors Greater
selectivity at blocking 5-Ht re-uptake than
norepinephrine re-uptake Lack Na channel
blocking (tricyclic action) so safer in
overdose Greater tolerability than
tricyclics All SSRIs are not the same Most
SSRIs bind to other receptors which are
also responsible for their clinical actions Each
SSRI has its own portfolio of effects
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Not-So Selective? (1) norepinephrine reuptake,
(2) dopamine reuptake, (3) serotonin-2C
receptors, (4) muscarinic cholinergic
receptors, (5) sigma receptors, (6) nitric
oxide synthase, (7) cytochrome P450 2D6, (8)
cytochrome P450 3A4, (9) cytochrome P450 1A2,
and (10) cytochrome P450 2Cl9.
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Review of the effects of 5 SSRIs A
meta-analysis of 20 short term comparative
studies of 5 SSRIs citalopram, fluoxetine,
fluvoxamine, paroxetine and sertralineNo
difference in efficacy between compoundsSlower
onset of action of fluoxetineFluoxetine may
cause more agitation, weight loss and
dermatological reactionsMore patients
discontinued fluvoxamine Fewer patients stopped
sertraline because of adverse effects than others
Edwards Anderson 1999
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Review of the effects of 5 SSRIs The most
common adverse reactions to the SSRIs
weregastrointestinal (nausea) and
neuropsychiatric - particularly headache and
tremorCommittee on Safety of Medicines more
reports of reactions to paroxetine, and of
gastrointestinal reactions to fluvoxamine and
paroxetinePrescription-event monitoring
revealed higher incidence of adverse events
related to fluvoxamine Fluoxetine not associated
with a higher incidence of suicidal, aggressive
and related events than the other SSRIs Edwards
Anderson 1999
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Review of the effects of 5 SSRIs Patients have
survived large overdoses of each of the
compoundsConcern expressed over 6 fatalities
following overdoses of citalopramCitalopram
should be avoided in patients likely to take
overdoses. Fluoxetine may not be the drug of
first choice for patients in whom a rapid
antidepressant effect is important or for those
who are agitated, Fluoxetine may have
advantages over other SSRIs in patients who are
poorly compliant with treatment and those who
have previously had troublesome discontinuation
symptomsFluvoxamine, and possibly paroxetine,
should not be used as first choice in patients
especially prone to SSRI-related adverse reactions
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Summary Role of Serotonin in behaviour can be
clearly defined Behaviours more complex than
just Serotonin SSRIs produce good results in
most patients SSRIs advanced over older
treatments SSRIs more complicated than just
Serotonin Re-uptake SSRIs get a bad press from
gen population and media Clinical use of SSRIs
requires careful balance of 5-HT in patient