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Psychopharmacology
therapeutics
The role of Serotonin
Dr. Craig Jackson
Senior Lecturer in Health Psychology
Faculty of Health
BCU
craig.jackson@bcu.ac.uk
Depressive Illness
Usually treatable
Common
Marked disability
Reduced survival
Increased costs
Depression may be
Coincidental association
Complication of physical illness
Cause of / exacerbate somatic symptoms
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.....
Impaired working and social lives and many unexplained physical symptoms
Greater use of medical services
“Walking Well”
Classification
Spectrum of mood disturbance
Mild thru to Severe
Transience
thru to
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”
Persistence
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
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
Classification of Depression (ICD-10)
Primary
Unipolar
 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
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

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
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
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

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
Substance misuse
Anti-hypertensive / Corticosteroid / Chemotherapy use
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 (MAOI’s)
rare fatalities
tyramine-free diet
Selective Serotonin Re-uptake Inhibitors (SSRI’s)
fluoxetine
lack sedation
no anticholinergic effects
improved compliance
less immediate benefit for disturbed sleep
safe in overdose
single or narrow range of doses works
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
Biology and Treatment of Aggression
History and Relationship with Suicidal Behaviour
The Role of Serotonin
The Role of Other Neurotransmitters & Hormones
Testosterone
Cholesterol
Opiates
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
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
CSF 5-HIAA and Aggression in Patients
n=15
n=9
00
5-HIAA ng/ml
20
40
60
Non-suicidal History
Suicidal History
0
4
8
12
16
20
Total Aggression Score
Brown et al. 1979
24
Psychopathology of Disruptive Behaviour Disorders
Trauma Related Disorders
Personality Disorders
DISRUPTIVE
BEHAVIOUR
DISORDERS
Mood & Affective Disorders
Stanford University, Division of Child Psychiatry
Substances
Violent Offender Studies
Low 5-HIAA
Impulsive Aggression
History of Suicide Attempts
Linoila et al. 1983
Suicide Studies
Low 5-HT Transporters
Low 5-HT2A Receptors
Stanley et al. 1982
Pharmacotherapy for Impulsive Aggression
Increase inhibitors
Increase 5-HT
Reduce Facilitators
Reduce Catecholamines (adrenaline, noradrenaline, dopamine)
SSRI’s can reduce CSF Vassopressin Levels (peptide hormone)
SSRI’s can reduce overt aggression (Coccaro & Kavoussi 1997)
“Ecstacy” and MDMA
Ecstacy stimulates serotonin
Produces cells which turn on the
areas of the prefrontal cortex
Give feelings of euphoria, meaning and affections
Regular users in danger of burning out the cells
Creating risk of temporary withdrawal symptoms and long-term risk of
chronic depression.
Serotonin and MDMA use
40 minute cognitive task
Frascella et al. 1999
Control
Chronic MDMA user
Serotonin Hypothesis
Pre-Synaptic 5-HT output reduced
Post-Synaptic receptor sensitivity increased
Serotonin Pathway
Serotonin Neurotransmission
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
Phentermine
Central Nervous System Stimulant
Similar to Dextroamphetamine
Benzeneethanamine, alpha, alpha-dimethyl
Fen-Phen
Fenfluramine & Phentermine
Combination therapy
Wyaeth-Ayerst (Fen) $190 M in 1996
FDA powerless to stop it
Some patients report anxiety, impulsion, aggression
Mood disorders are an illness - Treat them !
Drugs extremely effective
Concentration, mood, and thought
control restored
Mood stabilizing drugs
Role of Caffeine
Tranquillizers & Antipsychotics
acute episodic use only
E.C.T effectiveness
Too much Serotonin?
Increased 5-HT in CNS and receptor sites is therapeutic
Benefits in...
Depression
OCD
Panic Disorder
Bulimia
Toxic levels of 5-HT = fever, myoclonus, coma, seizure, cardiovascular
collapse and death
Fen-Phen related to cardiac damage - drug withdrawn
Too much Serotonin?
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 SSRI’s are not the same
Most SSRI’s bind to other receptors which are also
responsible for their clinical actions
Each SSRI has it’s own “portfolio” of effects
Not-So Selective?
(1) norepinephrine reuptake,
(3) serotonin-2C receptors,
(5) sigma receptors,
(7) cytochrome P450 2D6,
(9) cytochrome P450 1A2, and
(2) dopamine reuptake,
(4) muscarinic cholinergic receptors,
(6) nitric oxide synthase,
(8) cytochrome P450 3A4,
(10) cytochrome P450 2Cl9.
Review of the effects of 5 SSRI’s
A meta-analysis of 20 short term comparative studies of 5 SSRIs;
citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline
No difference in efficacy between compounds
Slower onset of action of fluoxetine
Fluoxetine may cause more agitation, weight loss and dermatological
reactions
More patients discontinued fluvoxamine
Fewer patients stopped sertraline because of adverse effects than others
Edwards & Anderson 1999
Review of the effects of 5 SSRI’s
The most common adverse reactions to the SSRIs were:
gastrointestinal (nausea) and neuropsychiatric - particularly headache and
tremor
Committee on Safety of Medicines: more reports of reactions to paroxetine,
and of gastrointestinal reactions to fluvoxamine and paroxetine
Prescription-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
Review of the effects of 5 SSRI’s
Patients have survived large overdoses of each of the compounds
Concern expressed over 6 fatalities following overdoses of citalopram
Citalopram 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 symptoms
Fluvoxamine, and possibly paroxetine, should not be used as first choice in
patients especially prone to SSRI-related adverse reactions
Summary
Role of Serotonin in behaviour can be clearly defined
Behaviours more complex than just Serotonin
SSRI’s produce good results in most patients
SSRI’s advanced over older treatments
SSRI’s more complicated than just Serotonin Re-uptake
SSRI’s get a bad press from gen population and media
Clinical use of SSRI’s requires careful balance of 5-HT in patient